Carbapenem antibacterial compounds, compositions containing such compounds and methods of treatment

ABSTRACT

Compounds of formula I are disclosed.                    
     as well as pharmaceutically acceptable salts thereof. The naphthosultam is substituted with various substituent groups including at least one cationic group -A-Q-L-B, wherein A-Q-L-B represents a side chain wherein: 
     A is a C 1-6  alkylene group, straight or branched, and optionally interrupted or terminated by 1-2 of —O—, —S—, NR a —, —C(O)— and —CH═CH—; 
     Q represents                    
      in which: 
     b is 2 or 3; 
     and X− is a charge balancing group; 
     L represents a C 1-8  alkylene group, unsubstituted or substituted with 1-3 R c  groups, and is interrupted or terminated by 1-3 of —CH═CH—, —C(O)—, —C(O)NR d —, —Het(R e )—, —C(O)—Het(R e )—, —C(O)NR a —Het(R e )—, —O—,—S—, —S(O)—, —SO 2 —, —CO 2 —, NR a —, —N + (R a ) 2 —                   
     B represents                    
     The carbapenems of the invention are effective against susceptible bacterial organisms, including methicillin resistant Staphylococcus aureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE), and methicillin resistant coagulase negative Staphylococci (MRCNS).

REFERENCE TO RELATED APPLICATION

This application claims the benefit of U.S. Provisional Application Ser.No. 60/063,031, filed Oct. 23, 1997. This is a continuation ofapplication Ser. No. 09/168,626 filed Oct. 8, 1998, now abandoned.

BACKGROUND OF THE INVENTION

The present invention relates to carbapenem antibacterial agents inwhich the carbapenem nucleus is substituted at the 2-position with anaphthosultam linked through a CH₂ group. The naphthosultam is furthersubstituted with various substituent groups including at least onecationic group -A-Q-L-B.

The carbapenems of the present invention are useful against grampositive microorganisms, especially methicillin resistant Staphylococcusaureus (MRSA), methicillin resistant Staphylococcus epidermidis (MRSE),and methicillin resistant coagulase negative Staphylococci (MRCNS), andare also active against Gram negative bacteria. There is an increasingneed for agents effective against such pathogens (MRSA/MRCNS) which areat the same time relatively free from undesirable side effects. Theantibacterial compounds of the present invention thus comprise animportant contribution to therapy for treating infections caused bythese difficult to control pathogens.

SUMMARY OF THE INVENTION

The present invention relates to a compound represented by formula I:

as well as pharmaceutically acceptable salts thereof, wherein:

R¹ represents H or methyl;

CO₂M represents a carboxylic acid, a carboxylate anion, apharmaceutically acceptable ester group or a carboxylic acid protectedby a protecting group;

P represents hydrogen, hydroxyl, F or hydroxyl protected by ahydroxyl-protecting group;

A-Q-L-B represents a side chain wherein:

A is a C₁₋₆ alkylene group, straight or branched, and optionallyinterrupted or terminated by 1-2 of —O—, —S—, NR^(a)—, —C(O)— and—CH═CH—;

Q represents

in which:

b is2or3;

and X− is a charge balancing counterion;

L represents a C₁₋₈ alkylene group, unsubstituted or substituted with1-3 R^(c) groups, and is interrupted or terminated by 1-3 of —CH═CH—,—C(O)—, —C(O)NR_(d)—, —Het(R^(e))—, —C(O)—Het(R^(e))—,—C(O)NR^(a)—Het(R^(e))—, —O—, —S—, —S(O)—, —SO₂—, —CO₂—, —NR^(a)—,—N⁺(R^(a))₂—

Het is a heteroaryl group;

B represents

wherein

represents a 5-10 membered mono- or bicyclic, N-containing heteroarylgroup, optionally containing 1-4 additional heteroatoms selected from O,S and N;

R^(a) is H or C₁₋₆ alkyl;

R^(b) is NH2 or C₁₋₆ alkyl unsubstituted or substituted with 1-3 groupsselected from halo, OH, CN and C(O)NH₂;

R^(c) is independently selected from halo, OR_(a), SR^(a), OC(O)R^(a),CO₂R^(a), CN, C(O)N(R^(a))2 and C(O)R^(a),

R_(d) is H or C₁₋₃ alkyl, or R^(c) and R_(d) taken together with anyintervening atoms represent a 4-6 membered ring;

R^(e) is H; R^(c); NO₂; N(R^(a))₂; SO₂N(R^(a))₂ or C₁₋₄ alkyl,unsubstituted or substituted with 1-3 groups selected from halo, OH andC(O)NH₂;

R^(f), R^(g) and R^(h) are independently selected from H; C₁₋₆ straightor branched chain alkyl, unsubstituted or substituted with 1-3 R^(c)groups; C₃₋₆ cycloalkyl, unsubstituted or substituted with 1-3 R^(c)groups; phenyl, unsubstituted or substituted with 1-3 R^(e) groups andHet, unsubstituted or substituted with 1-3 R^(e) groups,

or

R^(f) and R^(g) taken together with the intervening N atom form a 4-6membered ring, optionally interrupted by 1-2 of O, S, C(O) or NR^(h),and optionally substituted by 1-3 R^(c) groups;

and each R independently represents H; NO₂; N(R^(a))₂; SO₂N(R^(a))₂;R^(c) or C₁₋₄ alkyl, unsubstituted or substituted with 1-3 groupsselected from halo, OH, C(O)NH₂,

or

R together with A of the group -A-Q-L-B and any intervening atomsrepresent a 5-6 membered carbocyclic ring.

Pharmaceutical compositions and methods of treatment are also included.

DETAILED DESCRIPTION OF THE INVENTION

The invention is described herein in detail using the terms definedbelow unless otherwise specified.

Carboxylate anion refers to a negatively charged group —COO—.

The term “alkyl” refers to a monovalent alkane (hydrocarbon) derivedradical containing from 1 to 15 carbon atoms unless otherwise defined.It may be straight, branched or cyclic. Preferred alkyl groups includemethyl, ethyl, propyl, isopropyl, butyl, t-butyl, cyclopentyl andcyclohexyl. When substituted, alkyl groups may be substituted with up tofour substituent groups, selected from R^(c), R^(f) and R^(g), or asotherwise defined, at any available point of attachment. When the alkylgroup is said to be substituted with an alkyl group, this is usedinterchangeably with “branched alkyl group”. When a bond appears withouta group attached, this signifies the presence of a methyl group.

Cycloalkyl is a specie of alkyl containing from 3 to 15 carbon atoms,without alternating or resonating double bonds between carbon atoms. Itmay contain from 1 to 4 rings which are fused.

The term “alkenyl” refers to a hydrocarbon radical straight, branched orcyclic containing from 2 to 10 carbon atoms and at least one carbon tocarbon double bond. Preferred alkenyl groups include ethenyl, propenyl,butenyl and cyclohexenyl.

The term “alkynyl” refers to a hydrocarbon radical straight or branched,containing from 2 to 10 carbon atoms and at least one carbon to carbontriple bond. Preferred alkynyl groups include ethynyl, propynyl andbutynyl.

Aryl refers to aromatic rings e.g., phenyl, substituted phenyl and thelike, as well as rings which are fused, e.g., naphthyl, phenanthrenyland the like. An aryl group thus contains at least one ring having atleast 6 atoms, with up to five such rings being present, containing upto 22 atoms therein, with alternating (resonating) double bonds betweenadjacent carbon atoms or suitable heteroatoms. The preferred aryl groupsare phenyl, naphthyl and phenanthrenyl. Aryl groups may likewise besubstituted as defined. Preferred substituted aryls include phenyl andnaphthyl.

The term “heteroaryl” (Het) refers to a monocyclic aromatic hydrocarbongroup having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to10 atoms, containing at least one heteroatom, O, S or N, and in which1-2 additional carbon atoms are optionally replaced by a heteroatomselected from O or S, and in which from 1-3 additional carbon atoms areoptionally replaced by N, said heteroaryl group being optionallysubstituted as described herein. Examples include the following:

Heteroaryl includes protonated forms as well. It thus includespositively charged as well as non-charged groups. Examples include thegroups shown above, having an additional H attached to a nitrogen atom.

The group A-Q-L-B is attached to one of the two phenyl rings shown.

Heteroarylium refers to heteroaryl groups bearing a quaternary orprotonated atom and thus a positive charge. Examples include thefollowing:

When a charge is shown on a particular nitrogen atom in a ring or in anitrogen containing non-ring moiety which contains one or moreadditional nitrogen atoms, it is understood that the charge may resideon a different nitrogen atom than that shown in a particular drawing byvirtue of charge resonance that occurs.

Likewise, when a basic nitrogen containing moiety is provided at anappropriately acidic pH, the moiety becomes protonated due to acid basereactivity. Both the protonated and non-protonated forms of thecompounds of formula I are included in the present invention.

The term “heterocycloalkyl” refers to a cycloalkyl group (nonaromatic)in which one of the carbon atoms in the ring is replaced by a heteroatomselected from O, S or N, and in which up to three additional carbonatoms may be replaced by hetero atoms.

The terms “quaternary nitrogen” and “positive charge” refer totetravalent, positively charged atoms including, e.g., the positivelycharged nitrogen in a tetraalkylammonium group (e. g.tetramethylammonium), heteroarylium, (e.g., N-methyl-pyridinium), basicnitrogens which are protonated at physiological pH, and the like.Cationic groups thus encompass positively charged nitrogen-containinggroups, as well as basic nitrogens which are protonated at physiologicpH.

The term “heteroatom” means O, S or N, selected on an independent basis.

Halogen and “halo” refer to bromine, chlorine, fluorine and iodine.

Alkoxy refers to C₁-C₄ alkyl-O—, with the alkyl group optionallysubstituted as described herein.

When a group is termed “substituted”, unless otherwise indicated, thismeans that the group contains from 1 to 4 substituents thereon.

When a functional group is termed “protected”, this means that the groupis in modified form to preclude undesired side reactions at theprotected site. Suitable protecting groups for the compounds of thepresent invention will be recognized from the present application takinginto account the level of skill in the art, and with reference tostandard textbooks, such as Greene, T. W. et al. Protective Groups inOrganic Synthesis Wiley, New York (1991). Examples of suitableprotecting groups are contained throughout the specification.

In some of the carbapenem compounds of the present invention, M is areadily removable carboxyl protecting group, and/or P represents ahydroxyl which is protected by a hydroxyl-protecting group. Suchconventional protecting groups consist of groups which are used toprotectively block the hydroxyl or carboxyl group during the synthesisprocedures described herein. These conventional blocking groups arereadily removable, i.e., they can be removed, if desired, by procedureswhich will not cause cleavage or other disruption of the remainingportions of the molecule. Such procedures include chemical and enzymatichydrolysis, treatment with chemical reducing or oxidizing agents undermild conditions, treatment with a transition metal catalyst and anucleophile and catalytic hydrogenation.

Examples of carboxyl protecting groups include allyl, benzhydryl,2-naphthylmethyl, benzyl, silyl such as t-butyldimethylsilyl (TBDMS),phenacyl, p-methoxybenzyl, o-nitrobenzyl, p-methoxyphenyl,p-nitrobenzyl, 4-pyridylmethyl and t-butyl.

Examples of suitable hydroxyl protecting groups include triethylsilyl,t-butyldimethylsilyl, o-nitrobenzyloxycarbonyl,p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, allyloxycarbonyl,t-butyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl and the like.

The carbapenem compounds of the present invention are useful per se andin their pharmaceutically acceptable salt and ester forms for thetreatment of bacterial infections in animal and human subjects. The term“pharmaceutically acceptable ester, salt or hydrate,” refers to thosesalts, esters and hydrated forms of the compounds of the presentinvention which would be apparent to the pharmaceutical chemist. i.e.,those which are substantially non-toxic and which may favorably affectthe pharmacokinetic properties of said compounds, such as palatability,absorption, distribution, metabolism and excretion. Other factors, morepractical in nature, which are also important in the selection, are costof the raw materials, ease of crystallization, yield, stability,solubility, hygroscopicity and flowability of the resulting bulk drug.Conveniently, pharmaceutical compositions may be prepared from theactive ingredients in combination with pharmaceutically acceptablecarriers. Thus, the present invention is also concerned withpharmaceutical compositions and methods of treating bacterial infectionsutilizing as an active ingredient the novel carbapenem compounds.

With respect to —CO₂M, which is attached to the carbapenem nucleus atposition 3, this represents a carboxylic acid group (M represents H), acarboxylate anion (M represents a negative charge), a pharmaceuticallyacceptable ester (M represents an ester forming group) or a carboxylicacid protected by a protecting group (M represents a carboxyl protectinggroup). The pharmaceutically acceptable salts referred to above may takethe form —COOM, where M is a negative charge, which is balanced by acounterion, e.g., an alkali metal cation such as sodium or potassium.Other pharmaceutically acceptable counterions may be calcium, magnesium,zinc, ammonium, or alkylammonium cations such as tetramethylammonium,tetrabutylammonium, choline, triethylhydroammonium, meglumine,triethanolhydroammonium, etc.

The pharmaceutically acceptable salts referred to above also includeacid addition salts. Thus, the Formula I compounds can be used in theform of salts derived from inorganic or organic acids. Included amongsuch salts are the following: acetate, adipate, alginate, aspartate,benzoate, benzenesulfonate, bisulfate, butyrate, citrate, camphorate,camphorsulfonate, cyclopentanepropionate, digluconate, dodecylsulfate,ethanesulfonate, fumarate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, hydrochloride, hydrobromide,hydroiodide, 2-hydroxyethanesulfonate, lactate, maleate,methanesulfonate, 2-naphthalenesulfonate, nicotinate, oxalate, pamoate,pectinate, persulfate, 3-phenylpropionate, picrate, pivalate,propionate, succinate, tartrate, thiocyanate, tosylate and undecanoate.

The pharmaceutically acceptable esters are such as would be readilyapparent to a medicinal chemist, and include, for example, thosedescribed in detail in U.S. Pat. No. 4,309,438. Included within suchpharmaceutically acceptable esters are those which are hydrolyzed underphysiological conditions, such as pivaloyloxymethyl, acetoxymethyl,phthalidyl, indanyl and methoxymethyl, and others described in detail inU.S. Pat. No. 4,479,947. These are also referred to as “biolabileesters”.

Acid addition salts of the compounds of formula I are likely protonatedat physiological pH, as mentioned above. Compounds such as thosecontaining a basic N-containing moiety are capable of protonation inwater at or near pH 7, so that the moiety can exist in its neutral formor as an acid addition (protonated) form.

X− is a charge balancing group.

Biolabile esters are biologically hydrolizable, and may be suitable fororal administration, due to good absorption through the stomach orintenstinal mucosa, resistance to gastric acid degradation and otherfactors. Examples of biolabile esters include compounds in which Mrepresents an alkoxyalkyl, alkylcarbonyloxyalkyl,alkoxycarbonyloxyalkyl, cycloalkoxyalkyl, alkenyloxyalkyl, aryloxyalkyl,alkoxyaryl, alkylthioalkyl, cycloalkylthioalkyl, alkenylthioalkyl,arylthioalkyl or alkylthioaryl group. These groups can be substituted inthe alkyl or aryl portions thereof with acyl or halo groups. Thefollowing M species are examples of biolabile ester forming moieties:acetoxymethyl, 1-acetoxyethyl, 1-acetoxypropyl, pivaloyloxymethyl,1-isopropyloxycarbonyloxyethyl, 1-cyclohexyloxycarbonyloxyethyl,phthalidyl and (2-oxo-5-methyl-1,3-dioxolen-4-yl)methyl.

For the purposes of this invention, all compounds which have one or morecations are balanced with one or more, as necessary, of a chargebalancing group X⁻. Examples of cases where a charge balancing group isrequired are quarternized substituents such as heteroarylium orC(═N⁺R^(a)R^(f))R^(a), where R^(a) and R^(f) are not H. Additionally,all compounds having one or more anions are counter balanced with one ormore, as necessary, charge balancing cations.

When a group is interrupted by 2-3 of O, S, or N they cannot form O—O,O—O—O, O—S, O—S—O, S—S, or S—S—S bonds. This is exemplified in the casewhen L or A is an alkylene interrupted or terminated by 1-3 of O, S,—S(O)—, —SO₂—, NR^(a), CO₂ C(O)NR^(a), . . . and the like.

X⁻ can be present or absent as necessary to maintain the appropriatecharge balance. When present, these represent pharmaceuticallyacceptable counterions. Most anions derived from inorganic or organicacids are suitable. Representative examples of such counterions are thefollowing: acetate, adipate, aminosalicylate, anhydromethylenecitrate,ascorbate, aspartate, benzoate, benzenesulfonate, bromide, citrate,camphorate, camphorsulfonate, chloride, estolate, ethanesulfonate,fumarate, glucoheptanoate, gluconate, glutamate, lactobionate, malate,maleate, mandelate, methanesulfonate, pantothenate, pectinate,phosphate/diphosphate, polygalacturonate, propionate, salicylate,stearate, succinate, sulfate, tartrate and tosylate. Other suitableanionic species will be apparent to the ordinarily skilled chemist.

Likewise, when more than one negative charge is necessary to maintaincharge neutrality, the counterion indicator X⁻ represents a specie withmore than one negative charge, such as malonate, tartrate orethylenediaminetetraacetate (EDTA), or when a multivalent negativelycharged counterion is present with a carbapenem which bears a net singlepositive charge, an appropriate number of carbapenem molecules can befound in association therewith to maintain the overall charge balanceand neutrality.

Numbering and nomenclature using in naming the naphthosultams are asfollows:

Naphthosultam Nomenclature

The -A- portion of the side chain is a C₁₋₆ alkylene group which isstraight or branched, and is optionally interrupted or terminated by 1-2of O, S, NR^(a), C(O), and —CH═CH—. The interrupting groups can beseparate or together, and can terminate the C₁₋₆ alkylene group. Also,the interrupting or terminating moiety can be between the alkylene groupand the naphthosultam or -Q-. For example, A can represent —O—C₁₋₆alkyl-, —C₁₋₆ alkyl-O——NR^(a)—₁₋₆ alkyl- and the like.

Q represents

in which:

b is 2 or 3;

and X− is a charge balancing counterion.

L represents a C₁₋₈ alkylene group, unsubstituted or substituted with1-3 R^(c) groups, and is interrupted or terminated by 1-3 of —CH═CH—,—C(O)—, —C(O)NR_(d)—, —Het(R^(e))—, —C(O)—Het(R^(e))—, —C(O)NR^(a)—,—Het(R^(e))—, —O—, —S—, —S(O)—, —SO₂—, —CO₂—, —NR^(a)—, —N⁺(R^(a))₂—

These interrupting or terminating moieties can be separate or 15together. As described above with respect to A, the moieties can be atthe ends of the C₁₋₈ alkylene group, and between the C₁₋₈ alkylenemoiety and Q or B.

B represents

wherein

represents a 5-10 membered mono- or bicyclic, N-containing heteroarylgroup, optionally containing 1-4 additional heteroatoms selected from O,S and N. These include positively charged as well as neutral moieties,many of which become positively charged at neutral to acidic pH. All areincluded in the present invention.

When R^(b) represents C₁₋₆ alkyl, it may be unsubstituted or substitutedwith 1-3 groups selected from halo, OH, CN and C(O)NH₂.

When R^(c) and R_(d) both appear, they may be taken in combination withany intervening atoms to form a 4-6 membered ring.

When R^(f) and R^(g) are both present, they can be taken together withthe intervening atoms to form a 4-6 membered ring, which is optionallyinterrupted by 1-2 of O, S, C(O) and NR^(h). The ring can beunsubstituted or substituted with 1-3 R^(c) groups.

When one of the R groups is taken in combination with A from the sidechain A-Q-L-B, along with the intervening atoms, it represents a 5-6membered carbocyclic ring.

A subset of compounds of formula I which is of interest relates to thosecompounds where R¹ represents methyl. Within this subset, all othervariables are as originally defined.

Another subset of compounds of formula I which is of interest relates tothose compounds where CO₂M represents a carboxylate anion. Hence, M inthis instance represents a negative charge which is balanced by apositively charged group, such as in the positively charged Q group.

Another subset of compounds of formula I that is of interest relates tothose compounds where P represents hydroxyl or hydroxyl protected by ahydroxyl protecting group. Within this subset, all other variables areas originally defined.

Another subset of compounds of formula I that is of interest relates tocompounds of formula I wherein A represents C₁₋₃ alkylene. Within thissubset, all other variables are as originally defined.

Another subset of compounds of formula I that is of interest relates tocompounds where L is C₁₋₅ alkylene that is interrupted or terminated by—C(O)NR_(d)—, —C(O)NR^(a)—Het(R^(e))—, NR^(a)—, —N⁺(R^(a))₂ or

Within this subset, all other variables are as originally defined.

Another subset of compounds of formula I that is of interest relates tocompounds where B represents

Within this subset, all other variables are as originally defined.

A preferred subset of compounds of formula I which is of interestrelates to those compounds wherein:

R¹ represents methyl;

CO₂M represents a carboxylate anion;

P represents hydroxyl or hydroxyl protected by a hydroxyl protectinggroup;

A represents C₁₋₃ alkylene;

Q represents

in which:

b is 2 or 3,

and X− is a charge balancing counterion;

L is C₁₋₅ alkylene, interrupted or terminated by —C(O)NR_(d)—,—C(O)NR^(a)—Het(R^(e))—, —NR^(a)—, —N⁺(R^(a))₂— or

All other variables are as originally defined.

Representative examples of compounds of the invention are found inTables I-III.

TABLE I

wherein Q-L-B is selected from:

TABLE II

wherein Q-L-B is selected from:

TABLE III

wherein Q-L-B is selected from:

The process is illustrated by the following generic scheme:

With reference to Flow Sheet A above, P, R¹, R, and M, are as definedwith respect to the compounds of formula I.

P** represents a carboxyl protecting group.

Q* represents a group which reacts with intermediate A2 (upon activationof A2) in a manner which results in the incorporation in the finalproduct of a member of the group defined as Q above, thus Q* may beviewed as a precursor for Q.

The naphthosultam side chain group used in the synthesis of thecompounds of the present invention have, in some cases, been describedin the chemical literature. In other cases, precursor compounds whichmay be readily converted to the requisite naphthosultam have beendescribed in the literature. In cases where the requisite naphthosultamis not known in the literature it is neceessary to synthesize thenaphthosultam by a newly developed synthesis. One skilled in the art canadapt a previously published synthesis of an analogous naphthosultam toprepare the requisite compound in a straightforward manner without undueexperimentation. Examples of naphthosultam synthesis are describedherein (see below).

The naphthosultam side chain group is initially reacted with a suitablyprotected carbapen-2-em-3-carboxylate having an activated hydroxymethylgroup at the 2-position.

The carbapenem nucleus having a —CH₂OH substituent at position 2 can beobtained in accordance with Schmitt, S. M. et al., J. Antibiotics 41(6):780-787 (1988), the teachings of which are incorporated herein byreference. The carboxylic acid group at C-3 of the carbapenem isgenerally protected as a carboxyl protecting group such as p-nitrobenzyl(PNB), allyl, p-methoxybenzyl, trichloroethyl, 2-trimethylsilylethyl,and the like. Furthermore, the hydroxyl group of the 6-(hydroxyethyl)side-chain is optionally protected with a hydroxyl protecting group suchas trimethylsilyl (TMS), triethylsilyl (TES), tert-butyldimethylsilyl(TBDMS), tert-butyldiphenylsilyl (TBDPS), acetyl, allyloxycarbonyl,2-trimethylsilylethoxy carbonyl, 2-trichloroethoxycarbonyl and the like.

The addition of the naphthosultam side chain group to the carbapenem isaccomplished by treating a solution of the hydroxymethyl-carbapenem andthe naphthosultam side chain group in a suitable solvent such astetrahydrofuran (THF), ether, acetonitrile, dimethylformamide (DMF),benzene, dimethylsulfoxide (DMSO), and the like with a (premixed)suitable activating reagent such as diethyl azodicarboxylate(DEAD)/triphenylphosphine, diisopropyl azodicarboxylate(DIAD)/tributylphosphine, and the like, at a temperature between about−20° C. and 35° C. for about 5 to 90 minutes.

Alternatively, the naphthosultam and carbapenem can be mixed togetherwith either the azodicarboxylate or the phosphine reagent in a suitablesolvent and the other component of the activating reagent (the phosphineor the azodicarboxylate, respectively) can be added to that mixture.Once the naphthosultam, carbapenem, and activating reagent(s) have beenmixed, the reaction is allowed to proceed at a temperature between about−20° C. and 35° C. for about 5 to 90 minutes.

The resulting mixture is then subjected to a standard work-up procedurefamiliar to those skilled in the art to afford a crude2-naphthosultam-methyl substituted carbapenem which is purified, ifnecessary, by recrystallization or by chromatography on silica gel,eluting with a suitable solvent or mixture of two or more solvents, suchas hexane, ethyl acetate, ether, benzene, dichloromethane, chloroform,acetone, methanol and the like.

Modification of the naphthosultam side chain of compounds A2, which isgenerally necessary to introduce the charged substituent of A4, is bestaccomplished before removal of the protecting groups. For compoundswhich contain a hydroxyl group (X′) in the side chain, a positivelycharged substituent may be introduced into the side chain by firstactivating the hydroxyl group by converting it to a suitable leavinggroup (X) such as a triflate, mesylate, tosylate, iodide, chloride,bromide, and the like, and then displacing the resulting leaving groupwith a compound Q*, such as a suitably substituted diazabicyclooctane ora suitably substituted N,N-dimethylpiperazine. Alternatively, in somecases, the charged substituent may be incorporated in the naphthosultamside chain before addition of the naphthosultam to the carbapenem or maybe introduced after deprotection of A2. However, introduction of thecharged substituent by modification of A2 before deprotection is greatlypreferred.

In some cases, activation of the hydroxyl group and displacement by Q*to produce A3 may be accomplished in a single step by taking advantageof the basic character of compound Q* and using it as a base in theactivation reaction.

The conversion of the hydroxyl group to a suitable leaving group isaccomplished by treating the hydroxyl substituted compound in a suitablesolvent such as dichloromethane, tetrahydrofuran, ether, benzene, andthe like with an activating reagent, such as trifluoromethanesulfonicanhydride, methanesulfonic anhydride, toluenesulfonic anhydride,methanesulfonyl chloride, benzenesulfonyl chloride, toluenesulfonylchloride, and the like in the presence of a suitable base such astriethylamine, tributylamine, diisopropylethylamine, and the like at atemperature between about −100° C. and 0° C. for about 5 to 120 minutes.The intermediate thus obtained contains a leaving group, which may beconverted to an alternative leaving group, iodide, by treating asolution of the intermediate in a suitable solvent such as acetone,methyl ethyl ketone, and the like at about −10° C. to 50° C. with anexcess of sodium iodide or potassium iodide for about 0.25 to 24 hours.

In many cases, the iodide is obtained in sufficiently pure form that itmay be used without further purification. For ease of handling, theiodide, if not crystalline, may be lyophilized from benzene to afford anamorphous, easily handled, solid.

The activated hydroxyl group or iodide is displaced by reacting theactivated intermediate with reagent Q*. In some cases, activation anddisplacement of the hydroxyl group may be accomplished in a single step.The activating reagent is added to a solution of the hydroxylsubstituted compound in the presence of a suitable base in a suitablesolvent such as dichloromethane, tetrahydrofuran, ether, DMF, benzene,acetonitrile, DMSO, and the like as described in the precedingparagraphs. The resulting activated intermediate is treated with 1-3molar equivalents of compound Q* at a temperature between about −78° C.and 50° C. for about 15 to 120 minutes. In some cases, it is desirableto form the activated intermediate in one solvent, isolate the activatedintermediate, and conduct the displacement reaction in a differentsolvent. In other cases, the displacement may be conducted withoutisolation of the intermediate and, in cases where Q* is also used as abase, may even be concurrent with the formation of the activatedintermediate.

In cases where the displacement reaction is best accomplished by usingthe iodide, a solution of the iodide is combined with an approximatelyequivalent amount (0.9-1.05 molar equivalents) of compound Q*. A silversalt of a non-nucleophilic acid, such as silvertrifluoromethanesulfonate, silver tetrafluoroborate and the like is thenadded. Although the reaction will proceed in the absence of the silversalt, the reaction proceeds more rapidly in the presence of the silversalt. In addition, the silver salt assists in the removal of thedisplaced iodide from the reaction mixture which can improve theefficiency of subsequent steps. The resulting mixture is then subjectedto a standard work-up procedure familiar to those skilled in the art toafford a crude product which is purified, if necessary, byrecrystallization or chromatography.

The synthesis of the target compound is completed by removing anyprotecting groups which are present in the penultimate intermediateusing standard techniques which are well known to those skilled in theart. The deprotected final product is then purified, as necessary, usingstandard techniques such as ion exchange chromatography, HPLC on reversephase silica gel, MPLC on reverse phase polystyrene gel, and the like orby recrystallization.

The final product may be characterized structurally by standardtechniques such as NMR, IR, MS, and WV. For ease of handling, the finalproduct, if not crystalline, may be lyophilized from water to afford anamorphous, easily handled solid.

The compounds of the present invention are valuable antibacterial agentsactive against various Gram-positive and Gram-negative bacteria, andaccordingly find utility in human and veterinary medicine.

Many of compounds of the present invention are biologically activeagainst MRSA/MRCNS. In vitro antibacterial activity is predictive of invivo activity when the compounds are administered to a mammal infectedwith a susceptible bacterial organism.

Using standard susceptibility tests, the compounds of the invention aredetermined to be active against MRSA.

The invention is illustrated with the following non-limiting examples.

Preparative Example 1 SYNTHESIS OF4-(2-TRIETHYLSILANYLOXY-ETHYL)-1.8-NAPHTHOSULTAM

Step 1: 1-(2-Acetoxy-ethyl)-naphthalene

Triethylamine (691 mL, 4.96 mol) was added to an ice cold solution of1-(2-hydroxy-ethyl)-naphthalene (569 g, 3.30 mol) in dichloromethane(2.2 L). Acetyl chloride (282 mL, 3.97 mol) was added dropwise over 90minutes. After the addition was complete, the reaction mixture wasstirred for an additional 30 minutes with ice-bath cooling. The reactionmixture was washed sequentially with water (2×1 L), 1N HCl (1 L, 500mL), water (1 L), 5% aqueous NaHCO₃ (500 mL), water (1 L), and brine(500 mL), then dried over magnesium sulfate, filtered, and evaporated toafford 1-(2-acetoxy-ethyl)-naphthalene (723.2 g) as a yellow oil thatslowly crystallized.

Step 2: Potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate

Chlorosulfonic acid (69.3 g, 590 mmol) was added dropwise over 17minutes to a solution of 1-(2-acetoxy-ethyl)-naphthalene (105.5 g, 490mmol) in dichloromethane (200 mL). The reaction was exothermic andperiodic ice-bath cooling was employed to maintain the internaltemperature at 25-30° C. Approximately 10 minutes into the CLSO₃Haddition, voluminous evolution of HCl gas was observed. After theaddition was complete, the reaction mixture was stirred at roomtemperature for 3 hours then cautiously added to ice (400 g). Aftershaking, the layers were separated. The aqueous layer was washed withdichloromethane then slowly neutralized by addition of a solution ofpotassium carbonate (77 g, 560 mmol) in water (200 mL). The precipitatewas collected by filtration, washed with cold water (100 mL), then driedunder vacuum at 60 ° C. to afford potassium 4-(2-acetoxy-ethyl)naphthalene sulfonate (102.39 g) as a white solid. This materialcontained ca. 6% of the isomeric potassium5-(2-acetoxy-ethyl)-1-naphthalene sulfonate as determined by 1H NMR. Thefiltrate was concentrated under vacuum to afford a white suspension (355g) which was stored in a refrigerator overnight. The solid was collectedby filtration, washed with cold water (100 mL), then dried under vacuumat 60 ° C. to afford a second crop of potassium4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate (10.67 g) as a white solid.The second crop contained ca. 14% of the isomeric potassium5-(2-acetoxy-ethyl)-1-naphthalene sulfonate as determined by 1H NMR.

Step 3: 4-(2-Acetoxy-ethyl)-naphthalene-1-sulfonyl chloride

Potassium 4-(2-acetoxy-ethyl)-naphthalene-1-sulfonate (102.3 g, 308mmol) was added in portions over 15 minutes to a room temperaturesolution of dimethylformamide (2.4 mL, 31 mmol) in thionyl chloride (112mL, 1.54 mol). The reaction mixture was gradually brought to 80 ° C.(oil bath temperature) over 30 minutes and heated at 80° C. for 90minutes, then cooled to room temperature and stirred at room temperaturefor 60 minutes. The reaction mixture was partitioned between ice water(500 mL) and ethyl acetate (500 mL). The organic layer was washed withwater (200 mL) and brine (200 mL), dried over magnesium sulfate,filtered, and evaporated under vacuum to a cream colored solid. Thecrude product was triturated with pet ether to afford4-(2-acetoxy-ethyl)-naphthalene-1-sulfonyl chloride as a pale tan solid(77.47 g).

Step 4: 4-(2-Acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride

4-(2-Acetoxy-ethyl)-naphthalene-1-sulfonyl chloride (76.96 g, 246 mmol)was added portionwise over 12 minutes to 90% nitric acid (154 mL, 3.278mol) cooled in an ice-methanol bath (−20° C.). After the addition wascomplete, the reaction mixture was stirred at −20 ° C. for an additional15 minutes. The reaction mixture was partitioned between ice water (800mL) and chloroform (800 mL). The aqueous layer was extracted withchloroform (100 mL). The combined organic layers were washed with brine(400 mL, 200 mL), then dried over magnesium sulfate, filtered, andevaporated to a golden oil. Diethyl ether (300 mL) was added to thecrude product and the mixure was shaken vigorously to afford anoff-white solid. The solid was collected by filtration, washed withether (2×50 mL), and dried under vacuum to afford4-(2-acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride (41.85 g) asan off-white solid.

Step 5: 4-(2-Hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide

Solid 4-(2-acetoxy-ethyl)-8-nitro-naphthalene-1-sulfonyl chloride (39.64g, 111 mmol) was added to an ice-cold, 6.8 M solution of ammonia inmethanol (408 mL, 277 mmol). The cooling bath was removed, the reactionflask was stoppered, and the reaction was stirred at room temperature.After 4 days, the dark amber solution was concentrated under vacuum to adark gum. The residue was triturated vigorously shaken with water (300mL) to give a solid which was washed with water (150 mL) then ether (150mL) and dried under vacuum. The resulting brown solid was recrystallizedfrom isopropanol (300 mL) to afford4-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide (27.79 g) as tanflakes.

Step 6: 4-(2-Hydroxy-ethyl)-1,8-naphthosultam

Powdered cesium carbonate (76.8 g, 236 mmol) was added to a solution of4-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide (30.77 g, 94.3mmol) in anhydrous dimethylformamide (470 mL). The mixture was placedunder a nitrogen atmosphere, sonicated for 10 minutes, then stirred atroom temperature for 20 minutes. The mixture was then placed in a 100°C. oil bath and stirred vigorously. After 3.5 hours, the reactionmixture was removed from the heating bath, allowed to cool to roomtemperature, and left at room temperature overnight. The mixture wasthen filtered and the collected solid was washed with dimethylformamide.The combined filtrate and washings were evaporated to a dark oil. Thismaterial was dissolved in water (400 mL), treated with activatedcharcoal (5 g), and the resulting mixture was heated on a hot water bathfor 5 minutes. The mixture was cooled slightly then filtered through apad of super-cel. The filtrate was diluted with 2-butanone (450 mL),brine (300 mL), and 1M pH 1 aqueous phosphate (150 mL). The mixture wasshaken vigorously and the layers were separated. The aqueous layer wasextracted with 2-butanone (2×150 mL). The combined organic layers werewashed with brine (2×300 mL), dried over magnesium sulfate, filtered andevaporated to a brown solid (21.4 g). The solid was treated with ethylacetate (100 mL), sonicated for 15 minutes and filtered. The collectedsolid was washed with cold ethyl acetate (50 mL) and dried under vacuumto afford 4-(2-hydroxy-ethyl)-1,8-naphthosultam as a pale brown powder(16.68 g).

¹H NMR (DMSO-d₆, 500 MHz) d 3.25 (t, ArCH ₂CH₂OH), 3.73 (m, ArCH₂CH₂OH), 4.77 (t, ArCH₂CH₂OH), 6.90 (d, H-7), 7.58 (dd, H-6), 7.69 (d,H-5), 7.69 (d, H-3), and 8.03 (d, H-2).

Step 7: 4-(2-Triethlsilanyloxy-ethyl)-1,8-naphthosultam

Chlorotriethylsilane (13.57 mL, 80.86 mmol) was added dropwise over 1minute to a vigorously stirred suspension of4-(2-hydroxy-ethyl)-1,8-naphthosultam (17.53 g, 70.32 mmol) andimidazole (5.99 g, 87.90 mmol) in dichloromethane (351 mL). The reactionmixture was stirred under a nitrogen atmosphere at room temperature for15 minutes, then water (350 mL) was added. The organic layer was washedsequentially with 0.2 N HCl (350 mL) and water (350 mL) then dried overmagnesium sulfate, filtered, and evaporated under vacuum to a dark oil(29.07 g). The crude product was purified by flash column chromatographyon silica gel (5×27 cm column, eluted with 4:1 hexanes-EtOAc followed by3:1 hexanes-EtOAc) to afford a deep red oil (23.9 g). The oil was mixedwith hexanes (225 mL), sonicated to start crystallization, and stirredat room temperature. The mixture was filtered and the collected solidwas washed with hexanes (3×15 mL) and vacuum dried to afford4-(2-triethylsilyloxy-ethyl)-1,8-naphthosultam (19.78 g) as a lightpink-white solid.

¹H NMR (CDCl₃, 500 MHz) d 0.54 (q, SiCH ₂CH₃), 0.88 (t, SiCH₂CH ₃), 3.34(t, ArCH ₂CH₂O), 3.95 (t, ArCH₂CH ₂O), 6.89 (d, H-7), 7.14 (s, NH), 7.50(dd, H-6), 7.62 (d, H-3), 7.66 (d, H-5), 7.89 (d, H-2) mp 68.5-70.0° C.

Preparative Example 2 SYNTHESIS OF ALLYL(1S,5R,6S)-6-[(1R)-(ALLYLOXYCARBONYLOXY)-ETHYL]-1-METHYL-2-{4-[2-(TRIFLUOROMETHANESULFONYLOXY)-ETHYL]-1,8-NAPHTHOSULTAMYL-METHYL}-CARBAPEN-2-EM-3-CARBOXYLATE

Step 1: Allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-{1(R)-methyl-2-oxo-3-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-propyl}-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate

A solution of allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-[3-hydroxy-1(R)-methyl-2-oxo-propyl]-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate(74.8 g, 116.2 mmol), 4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultam(38.03 g, 104.6 mmol), and triphenylphosphine (45.72 g, 174.3 mmol) inanhydrous tetrahydrofuran (582 mL) was placed under a nitrogenatmosphere and cooled in an ice bath. Diisopropyl azodicarboxylate (34.3mL, 174.3 mmol) was added over one minute. The resulting solution wassirred at 0° C. for 60 minutes followed by 30 minutes at roomtemperature. The mixture was filtered to remove a small amount of solid.The filtrate was diluted with ethyl acetate (300 mL) and washed withbrine (300 mL). The organic phase was dried over magnesium sulfate,filtered and evaporated under vacuum to a dark red oil (220.1 g). Thecrude product was purified by chromatography on silica gel (5 kg),eluting with 7:3 hexane-ethyl acetate followed by 1:1 hexane-ethylacetate. The product containing fractions were combined and evaporatedunder vacuum to afford the title compound (94.7 g) as a viscous oil. Inorder to determine an accurate yield for the reaction, an aliquot ofthis material (508.8 mg of 263.5 g of a solution of the product intoluene) was lyophilized from benzene to afford an off-white fluffysolid (144.1 mg). The actual yield of product was calculated as 74.62 g.

Step 2: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate

A solution of allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-{1(R)-methyl-2-oxo-3-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-propyl}-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate(74.6 g, 75.4 mmol, see step 1) in toluene (750 mL) was placed under anitrogen atmosphere and refluxed for 2.5 hours. The reaction mixture wasallowed to cool to room temperature and evaporated to a paste which wasstored overnight in the freezer as a suspension in dichloromethane. Thecrude product was purified by chromatography on silica gel (1.8 kg),eluting with 85:15 hexane-ethyl acetate followed by 4: hexane-ethylacetate. The product containing fractions were combined and evaporatedunder vacuum to afford the title compound (42.4 g) as a viscous tan oil.

IR (thin film on NaCl) 2955, 2876, 1784, 1746, 1716, 1258, and 661 cm⁻¹

¹H NMR (CDCl₃, 500 MHz) d 0.52 (q, SiCH ₂CH₃), 0.88 (t, SiCH₂CH ₃) 1.29(d, 1-CH₃), 1.43 (d, CH ₃CHOCO₂), 3.34 (t, ArCH ₂CH₂O), 3.37 (dq, H-1),3.43 (dd, H-6), 3.94 (t, ArCH₂CH ₂O), 4.14 (dd, H-5), 4.56-4.60 (m,OCO₂CH₂), 4.67 (d, 2-CHaHb), 4.81 and 4.92 (two dd, CO₂CH₂), 5.11 (dq,CH₃CHOCO₂), 5.24 (d, vinyl-H) 5.30-5.34 (m, 2 vinyl-H), 5.37 (d,2-CHaHb), 5.50 (d, vinyl-H), 5.86-5.89 (m, vinyl-H), 6.00-6.04 (m,vinyl-H), 6.69 (d, Ar H-7), 7.50 (t, Ar H-6), 7.61 (d, Ar H-5), 7.63 (d,Ar H-3), 7.90 (d, Ar H-2)

HRMS (FAB) calculated for C₃₆H₄₇N₂O₉SiS (MH⁺) 711.2771; found 711.2690.

Step 3: Allyl(1S,5R,6S)-6-[1(1R)-(allyloxycarbonyloxy)-ethyl]-2-[4-(2-hydroxy-propyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2-em-3-carboxylate

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-[4-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate(45.2 g, 63.6 mmol) in tetrahydrofuran (500 mL) was diluted with water(125 mL) and treated with 1M aqueous trifluoromethanesulfonic acid (6.4mL, 6.4 mmol). The resulting mixture was stirred at room temperature for15 minutes, then partitioned between 5% aqueous sodium bicarbonate (200mL), brine (25 mL), and ethyl acetate (500 mL). The organic phase waswashed with dilute brine (200 mL), dried over magnesium sulfate,filtered and evaporated under vacuum to an oil (50.2 g). The oil wasevaporated under vacuum from toluene (3×50 mL) to afford the titlecompound (42.9 g) as a tacky foam. This material was used withoutpurification in the next step.

¹H NMR (CDCl₃) d 1.31 (d, 1-CH₃), 1.45 (d, CH 3CHOCO₂), 3.41 (t, ArCH₂CH₂OH), 3.41 (dq, H-1), 3.45 (dd, H-6), 4.04 (dt, ArCH₂CH ₂OH), 4.16(dd, H-5), 4.59 (m, OCO₂CH₂), 4.69 (d, 2-CHaHb), 4.89 (m, CO₂CH₂), 5.14(dq, CH₃CHOCO₂), 5.26, 5.33, 5.35 and 5.53 (four m, 4 vinyl-H), 5.41 (d,2-CHaHb), 5.91 and 6.05 (two m, 2 vinyl-H), 6.73 (d, Ar H-7), 7.54 (dd,Ar H-6), 7.63 (d, Ar H-5), 7.68 (d, Ar H-3), 7.95 (d, Ar H-2)

Step 4: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{4-[2-(trifluoromethanesulfonyloxy)-ethyl]-1,8-naphthosultamyl-methyl}-carbapen-2-em-3-carboxylate

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[4-(2-hydroxy-propyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2-em-3-carboxylate(63.58 mmol, amount teoretically present in the unpurified product ofthe previous step) in anhydrous methylene chloride (750 mL) was placedunder a nitrogen atmosphere, cooled in an ice-methanol bath (−15° C.),and treated with 2,6-lutidine (22.2 mL, 190.7 mmol). The resultingmixture was aged at −15° C. for 8 minutes then trifluoromethanesulfonicanhydride (16.0 mL, 95.4 mmol) was added over a period of 4 minutes.After 30 minutes at −15° C., the reaction mixture was diluted withmethylene chloride (1.25 L) and washed sequentially with water (1.8 L),0.2N hydrochloric acid (2×1.8 L) and water (1.8 L), then dried overmagnesium sulfate, filtered, and evaporated under vacuum to give thetitle compound as an oil.

¹H NMR (CDCl₃, 500 MHz) δ1.31 (d, 1-CH ₃), 1.44 (d, CH ₃CHOH), 3.39 (m,H-1), 3.45 (dd, H-5), 3.67 (CH ₂CH₂OTf), 4.16 (m, H-6), 4.58 (t,CH₂OTf), 4.67 (d, 2-CHaHb), 4.82 (m, CH ₂CH═CH₂), 4.93 (m, CH₂CH═CH ₂),5.12 (m, CHCH₃O), 5.24 (d, CH ₂CH═CH₂), 5.32 (m, CH₂CH═CH ₂), 5.41 (d,CH₂N), 5.52 (d, CH ₂CH═CH₂), 5.88 (m, CH₂CH═CH₂), 6.03 (m, CH₂CH═CH₂),6.77 (d, ArH-7), 7.54 and 7.58 (2 m's, ArH-5 and Ar H-6), 7.67 (d, ArH-2), 7.96 (d, Ar H-4).

Preparative Example 3 SYNTHESIS OF3-(2-TRIETHYLSILANYLOXY-ETHYL)-1,8-NAPHTHOSULTAM

Step 1: 1-Bromo-²-(2-hydroxy-ethyl)naphthalene

A solution of 2-(2-hydroxy-ethyl)-naphthalene (58.5 g, 0.34 mol) inanhydrous acetonitrile (500 mL) was treated with N-bromo-succinimide(66.5 g, 0.37 mol). The resulting solution was stirred at roomtemperature under a nitrogen atmosphere and protected from light for 30minutes, then heated in an oil bath at 50° C. for 2 hours. After coolingto room temperature, the reaction mixture was evaporated under vacuum toa viscous oil. The oil in diethyl ether (350 mL) was washed with water(350 mL), dilute aqueous sodium thiosulfate (300 mL), water (300 mL) andbrine (200 mL), dried over magnesium sulfate, filtered, and evaporatedunder vacuum to an oil (89.5 g) that solidified on standing. The crudeproduct was chromatographed on a column of EM silica gel 60, elutingwith methylene chloride, to afford a yellow solid (78.2 g).Recrystallization of this material from carbon tetrachloride providedthe title compound (46.5 g) as a pale yellow solid.

Step 2: 2-(2-Acetoxy-ethyl)-1-bromo-naphthalene

A solution of 1-bromo-2-(2-hydroxy-ethyl)-naphthalene (46.5 g, 0.185mol) in methylene chloride (370 mL) was placed under a nitrogenatmosphere, cooled in an ice bath, and stirred. Triethylamine (32.3 mL,0.232 mol) was added followed by acetyl chloride (15.8 mL, 0.222 mol)dropwise over 5 minutes. The reaction mixture was removed from the icebath and stirred at room temperature for 15 minutes. The reactionmixture was washed with water (300 mL), 1N hydrochloric acid (200 mL)and water (250 mL), dried over magnesium sulfate, filtered, andevaporated under vacuum to afford the title compound as an oil (55.1 g).

Step 3: Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonate

A solution of 2-(2-acetoxy-ethyl)-1-bromo-naphthalene (32.5 g, 0.111mol) in trifluoroacetic acid (111 mL) was stirred under a nitrogenatmosphere and cooled in an ice bath while chlorosulfonic acid (8.9 mL,0.130 mol) was added dropwise over 5 minutes. The resulting solution washeated in an oil bath at 50° C. for 90 minutes then cooled to roomtemperature and evaporated under vacuum to dark oil. The oil waspartitioned between methylene chloride (150 mL) and water (150 mL). Theaqueous phase was washed with methylene chloride (150 mL), brieflypumped under vacuum, then brought to pH 8 with 3M aqueous potassiumhydroxide (30 mL) followed by 4M aqueous potassium carbonate (35 mL).The resulting mixture was stirred in a cold room (5° C.) for 2 hours andfiltered to remove the product. The recovered white solid was vacuumdried to afford the title compound (11.21 g).

Step 4: 3-(2-Acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonyl chloride

Potassium 3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonate (17.75 g,43.2 mmol) was added at room temperature to a stirred solution ofN,N-dimethylformamide (0.334 mL, 4.31 mmol) in thionyl chloride (63 mL,863 mmol). The resulting mixture was placed in an oil bath at 70° C. andstirred. After 10 minutes, additional thionyl chloride (20 mL) was addedto facilitate stirring. After 40 minutes at 70°, the reaction flask wasfitted with a distillation head and excess thionyl chloride was removedunder vacuum. The residual brown solid was mixed with diethyl ether (300mL) and added to an ice-cold, stirred mixture of water (100 mL) andether (100 mL). The organic phase was separated, washed with water (200mL) and brine (100 mL), dried over magnesium sulfate, filtered, andevaporated under vacuum to afford the title compound (14.63 g).

Step 5: 3-(2-Acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonylchloride

An ice-cold, stirred solution of3-(2-acetoxy-ethyl)-4-bromo-naphthalene-1-sulfonyl chloride (17.66 g,45.1 mmol) in trifluoroacetic acid (150 mL) was treated with 96%sulfuric acid (12.5 mL, 225 mmol) and with 90% nitric acid (2.65 mL,56.4 mmol) added dropwise over 3 minutes. The reaction mixture wasremoved from the ice bath, stirred at room temperature for 15 minutes,re-cooled in an ice bath, and treated with water (850 mL) addeddropwise. The resulting mixture was filtered through a celite pad tocollect the solid which was washed with water (100 mL) and dissolved inmethylene chloride (350 mL). The methylene chloride solution was washedwith water (500 mL) containing brine (100 mL), dried over magnesiumsulfate, and evaporated under vacuum to an oil (21.23 g). This materialwas shown to be a 42:58 mixture of the 5-NO₂ to 8-NO₂ products by ¹HNMR). The crude product was mixed with ethyl acetate (20 mL) andsonicated to provide a crystalline precipitate. This material wascollected, washed with ethyl acetate, and dried under vacuum to affordthe title compound (8.11 g) as an off-white solid. The mother liquorsyielded an additional 1.47 g of the title compound following flashchromatography on silica gel (eluting with 30-35% ethyl acetate inhexane) and crystallization from diethyl ether.

Step 6: 3-(2-Acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonamide

Solid 3-(2-acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonylchloride (5.00 g, 11.45 mmol) was added at room temperature to 0.5Mammonia in dioxane (92 mL, 46 mmol). After stirring at room temperaturefor 40 minutes, the mixture was evaporated under vacuum to a residuewhich was mixed with water (100 mL), sonicated, and filtered. Thecollected pale-yellow solid was washed with water (2×20 mL) and vacuumdried to afford the title compound (4.75 g).

Step 7: 4-Bromo-3-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide

Sodium methoxide in methanol (23.7 mL of a 0.5M solution, 11.8 mmol) wasadded to a suspension of3-(2-acetoxy-ethyl)-4-bromo-8-nitro-naphthalene-1-sulfonamide (4.70 g,11.3 mmol) in methanol (33 mL). The mixture was stirred under a nitrogenatmosphere at room temperature for 90 minutes, then concentrated undervacuum to approximately half volume, diluted with ethyl acetate (200mL), and washed with 2N hydrochloric acid. The oganic solution waswashed with water (100 mL) and brine (50 mL), dried over magnesiumsulfate, filtered, and left to stand at room temperature. The organicsolution deposited a solid which was collected by filtration, washedwith ethyl acetate (2×15 mL), and vacuum dried to give the title comound(1.78 g). Additional poduct (1.88 g) was obtained from the motherliquors after concentration under vacuum and crystallization fromdiethyl ether.

Step 8: 4-Bromo-3-(2-hydroxy-ethyl)-1,8-naphthosultam

A solution of4-bromo-3-(2-hydroxy-ethyl)-8-nitro-naphthalene-1-sulfonamide (3.61 g,9.62 mmol) in anhydrous N,N-dimethylformamide (96 mL) was treated withcesium carbonate (7.84 g, 24.1 mmol). The resulting mixture placed undera nitrogen atmospere, sonicated at room temperature for 10 minutes,stirred at room temperature for 5 minutes, and then heated in an oilbath at 100° C. for 2 hours. The mixture was evaporated under vacuum toa brown residue which was partitioned between ethyl acetate (100 mL) and2N hydrocloric acid (20 mL). The organic phase was washed with water (20mL) and brine (20 mL), dried over magnesium sulfate, filtered, andevaporated under vacuum to a solid (2.83 g). This material was mixedwith diethyl ether (30 mL), sonicated, stirred, and filtered. Thecollected solid was washed with ether (20 mL) and vacuum dried to givethe title compound (2.21 g) as a tan powder.

Step 9: 3-(2-Hydroxy-ethyl)-18-naphthosultam

A solution of 4-bromo-3-(2-hydroxy-ethyl)-1,8-naphthosultam (2.10 g, 6.4mmol) in ethanol (105 mL) was treated with triethylamine (2.68 mL, 19.2mmol) and 20% palladium hydroxide on carbon (0.84 g). The mixture washydrogenated (45-50 psi H₂) on a Parr shaker for 6.5 hours at roomtemperature, then filtered through a celite pad to remove the catalystwhich was washed with additional ethanol (3×5 mL). The filtrate andwashings were evaporated under vacuum to a residue which was partitionedbetween ethyl acetate (60 mL) and 1N hydrochloric acid (50 mL). Theorganic phase was washed with brine (25 mL), dried over magnesiumsulfate, filtered, and evaporated under vacuum to afford the titlecompound (1.32 g) as a brown solid.

Step 10: 3-(2-Triethylsilanyloxy-ethyl)-1,8-naphthosultam

A mixture of 3-(2-hydroxy-ethyl)-1,8-naphthosultam (1.44 g, 5.78 mmol)and imdazole (0.495 g, 7.27 mmol) in anhydrous methylene chloride (39mL), at room temperature and under a nitrogen atmosphere, was treatedwith chlorotriethylsilane (1.12 mL, 6.69 mmol). After stirring at roomtemperature for 30 minutes, the mixture was diluted with methylenechloride (60 mL), washed with water (100 mL), 0.2N hydrochloric acid (50mL) and water (100 mL), dried over magnesium sulfate, filtered, andevaporated under vacuum to a dark oil (2.15 g). The oil was purified byflash chromatography on EM silica gel 60 (4×15 cm column), using 3:1hexane-ethyl acetate as eluting solvent, to give an oil (2.09 g). Thismaterial was mixed with hexane (10 mL) and sonicated to afford acrystalline solid. The solid was collected, washed with hexane (3 mL),and dried to afford the title compound (1.73 g).

MP. 97.5-98.0° C.

¹H NMR (CDCl₃) d 0.54 (q, SiCH ₂CH₃), 0.88 (t, SiCH₂CH ₃), 3.08 (t,ArCH₂), 3.90 (t, CH₂O), 6.84 (m, H-7), 7.24-7.47 (m, H-5 and H-6), 7.84and 7.90 (two d's, H-2 and H-4).

Preparative Example 4 SYNTHESIS OF ALLYL(1S,5R,6S)-6-[(1R)-(ALLYLOXYCARBONYLOXY)-ETHYL]-1-METHYL-2-{3-[2-(TRIFLUOROMETHANESULFONYLOXY)-ETHYL]-1,8-NAPHTHOSULTAMYL-METHYL}-CARBAPEN-2-EM-3-CARBOXYLATE

Step 1: Allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-{1(R)-methyl-2-oxo-3-[3-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-propyl}-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate

A solution of allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-[3-hydroxy-1(R)-methyl-2-oxo-propyl]-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate(3.81 g, 5.91 mmol), 3-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultam(1.72 g, 4.78 mmol), and triphenylphosphine (2.32 g, 8.87 mmol) inanhydrous tetrahydrofuran (30 mL) was placed under a nitrogen atmosphereand cooled in an ice bath. Diisopropyl azodicarboxylate (1.75 mL, 8.87mmol) was added over one minute. The resulting solution was sirred at 0°C. for 60 minutes followed by 30 minutes at room temperature, thendiluted with ethyl acetate (100 mL) and washed with brine (50 mL). Theorganic phase was dried over magnesium sulfate, filtered and evaporatedunder vacuum to a viscous, dark oil. The crude product was purified byflash chromatography on EM silica gel 60 (5×19 cm column), eluting with2:1 hexane-ethyl acetate. The product containing fractions were combinedand evaporated under vacuum to afford the title compound (3.48 g) as afoam.

Step 2: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-[3-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate

A solution of allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-{1(R)-methyl-2-oxo-3-[3-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl]-propyl}-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate(3.47 g, 3.50 mmol) in anhydrous toluene (35 mL) was placed under anitrogen atmoshere and heated at reflux for 3.5 hours. The solution wasconcentrated under vacuum to 10 mL and applied to a column (4×20 cm) ofEM silica gel 60. The column was eluted with 3:1 hexane-ethyl acetate(28×20 mL fractions) followed by 2:1 hexane-ethyl acetate (20 mLfractions). The product containing fractions were combined andconcentrated under vacuum. The residue was lyophilized from benzene togive the title compound (1.894 g) as a gum.

¹H NMR (CDCl3) d 0.57 (q, SiCH ₂CH₃), 0.92 (t, SiCH₂CH ₃), 1.31 (d,1-CH₃), 1.45 (d, CH ₃CHOCO₂), 3.11 (t, ArCH ₂CH₂O), 3.41 (dq, H-1), 3.45(dd, H-6), 3.93 (t ArCH₂CH ₂O), 4.17 (dd, H-5), 4.59 (m, OCO₂CH₂), 4.67(d, 2-CHaHb), 4.81-4.95 (m, CO₂CH₂), 5.14 (dq, CH₃CHOCO₂), 5.25-5.36 (m,3 vinyl-H), 5.39 (d, 2-CHaHb), 5.50-5.54 (m, vinyl-H), 5.88-5.93 (m,vinyl-H), 6.01-6.07 (m, vinyl-H), 6.66 (d, Ar H-7), 7.43 (d, Ar H-5),7.48 (dd, Ar H-6), 7.90 and 7.93 (two s, Ar H-2 and Ar H-4).

Step 3: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[3-(2-hydroxy-propyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2-em-3-carboxylate

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-[3-(2-triethylsilanyloxy-ethyl)-1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate(0.502 g, 0.706 mmol) in tetrahydrofuran (5.6 mL) was diluted with water(1.4 mL) and treated with 1M aqueous trifluoromethanesulfonic acid(0.071 mL, 0.071 mmol). After stirring at room temperature for 15minutes, the solution was treated with 2% aqueous sodium bicarbonate (5mL) and extracted with ethyl acetate (25 mL). The organic phase waswashed with brine (25 mL), dried over magnesium sulfate, filtered andevaporated under vacuum to provide the title compound (0.473 g) as anoil.

¹H NMR (CDCl₃) d 1.31 (d, 1-CH₃), 1.45 (d, CH ₃CHOCO₂), 3.16 (t, ArCH₂CH₂OH), 3.40 (dq, H-1), 3.45 (dd, H-6), 4.01 (q, ArCH₂CH ₂OH), 4.16(dd, H-5), 4.59 (m, OCO₂CH₂), 4.67 (d, 2-CHaHb), 4.81-4.95 (m, CO₂CH₂),5.13 (dq, CH₃CHOCO₂), 5.25-5.36 (m, 3 vinyl-H), 5.40 (d, 2-CHaHb),5.50-5.54 (m, vinyl-H), 5.88-5.93 (m, vinyl-H), 6.02-6.07 (m, vinyl-H),6.68 (d, Ar H-7), 7.45 (d, Ar H-5), 7.50 (dd, Ar H-6), 7.91 and 7.96(two s's, Ar H-2 and Ar H-4).

Step 4: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{3-[2-(trifluoromethanesulfonyloxy)-ethyl]-1,8-naphthosultamyl-methyl}-carbapen-2-em-3-carboxylate

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[3-(2-hydroxy-propyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2-em-3-carboxylate(0.706 mmol) and 2,6-lutidine (0.246 mL, 2.12 mmol) in anhydrousmethylene chloride (9.4 mL) was placed under a nitrogen atmosphere andcooled in a CCl₄-dry ice bath (−23° C.).

Trifluoromethanesulfonic anhydride (0.178 mL, 1.06 mmol) was added andthe resulting solution was stirred in the cold for 30 minutes. Thesolution was diluted with methylene chloride (20 mL) and water (20 mL)and shaken. The organic phase was separated, washed with 0.2Nhydrochloric acid (20 mL) and water (20 mL), dried over magnesiumsulfate, filtered and evaporated under vacuum to give the title compoundas a foam (0.531 g).

¹H NMR (CDCl₃) d 1.32 (d, 1-CH₃), 1.46 (d, CH ₃CHOCO₂), 3.41 (dq, H-1),3.44 (t, ArCH ₂CH₂O), 3.45 (dd, H-6), 4.18 (dd, H-5), 4.56-4.64 (m,OCO₂CH₂), 4.63 (d, 2-CHaHb), 4.83 (t, ArCH₂CH ₂O), 4.8-4.96 (m, CO₂CH₂),5.14 (dq, CH₃CHOCO₂), 5.25-5.36 (m, 3 vinyl-H), 5.42 (d, 2-CHaHb),5.51-5.54 (m, vinyl-H), 5.86-5.95 (m, vinyl-H), 6.02-6.09 (m, vinyl-H),6.73 (d, Ar H-7), 7.48 (d, Ar H-5), 7.55 (dd, Ar H-6), 7.86 and 7.97(two S's, Ar H-2 and Ar H-4).

Preparative Example 5 SYNTHESIS OF4-(TRIETHYLSILYLOXY-METHYL)-1,8-NAPHTHOSULTAM

Step 1: Potassium 4-bromo-naphthalene-1-sulfonate

A solution of 1-bromonaphthalene (19 mL, 137 mmol) in carbontetrachloride (24 mL) was cooled in an ice bath under nitrogen.Chlorosulfonic acid (9.1 mL, 137 mmol) was added dropwise over 20minutes. After an additional 5 minutes, the heavy grey suspension wasremoved from the ice bath and was stirred at room temperature for 16hours to give a grey paste. The mixture was partitioned betweenmethylene chloride (100 mL) and water (300 mL). The aqueous layer wasmade basic with potassium carbonate and the resulting suspension wasfiltered. The collected solid was washed with methylene chloride (50 mL)and water (50 mL), and dried under vacuum to give the title compound asa white solid (30 g).

¹H NMR (DMSO-d6) d 7.61 (m, ArH), 7.65 (m, ArH), 7.82 (m, 2ArH), 8.14(dd, ArH), and 8.90 (dd, ArH).

Step 2: 4-Bromo-8-nitro-naphthalene-1-sulfonic acid

Potassium 4-bromo-naphthalene-1-sulfonate (1.38 g, 4.24 mmol) was addedportionwise over 20 minutes to 90% nitric acid (2 mL), which was cooledin a methanol/ ice bath to approximately −15 ° C. After 1.5 hours, themixture was placed in a refrigerator for 20 hours. Diethyl ether (20 mL)was added and the precipitated solid was filtered, washed with ether(100 mL) and isopropanol (20 mL), and dried under a stream of nitrogento give the title compound as an approximately 4:1 mixture of the 5- and8-nitro isomers (1.25 g).

¹H NMR (D₂O) d 7.70 (dd, ArH), 8.09 (d, ArH), 8.20 (d, ArH), 8.21 (dd,ArH), and 8.63 (d, ArH).

Step 3: Sodium 4-bromo-8-amino-naphthalene-1-sulfonate

4-Bromo-8-nitro-naphthalene-1-sulfonic acid (1 g, 3.01 mmol) and tinchloride dihydrate (1.83 g, 8.1 mmol) were suspended in a mixture ofwater (10 mL) and ethanol (10 mL). The resulting mixture was heated for3 hours in a 100° C. oil bath. The mixture was cooled to roomtemperature and filtered. The collected solid was suspended in water (20mL) and the mixture was made basic with sodium carbonate then placed ona CG161 amberchrom resin column (3×9 cm). The column was washed withwater (300 mL) and was eluted with 25% MeCN/H₂O, collecting 12 mLfractions. Fractions 17-19 were combined and evaporated to give thetitle compound as a solid (0.33 g).

¹H NMR (D₂O) d 7.07 (dd, ArH), 7.49 (t, ArH), 7.83 (d, ArH), 7.85 (ddArH) and 8.08 (d, ArH).

Step 4: 4-Bromo-1,8-naphthosultam

Sodium 4-bromo-8-amino-naphthalene-1-sulfonate (1.2 g, 3.70 mmol) wassuspended in phosphorous oxychloride (10 mL, 107 mmol) and the mixturewas refluxed for 1 hour to give a thin suspension. The mixture wascooled to room temperature and was added to ice (100 mL). Theprecipitate was collected and washed with water (20 mL) then dried undervacuum (0.675 g). A second crop was obtained from the filtrate (0.186g). The combined solids were dissolved in 5% methanol in methylenechloride and were placed on a silica gel column (29×3.5cm, packed andeluted with 5% methanol in methylene chloride), collecting 8 mLfractions. Fractions 27-39 were combined and evaporated to give thetitle compound as a solid (0.55 g).

¹H NMR (0.14 mL CDCl₃ and 0.01 mL CD₃OD) d 6.89 (d, ArH), 7.58(dd ArH),7.68 (d, ArH), 7.73 (d, ArH) and 7.95 (d, ArH).

Step 5: 4-Formyl-1,8-naphthosultam

A solution of 4-bromo-1,8-naphthosultam (0.24 g, 0.845 mmol) inanhydrous tetrahydrofuran (5 mL) was cooled in a dry ice/acetone bathunder nitrogen. n-Butyllithium (1.32 mL of a 1.6 M solution in hexanes,2.11 mmol) was added and the mixture was stirred for 5 minutes. Ethylformate (1 mL, 12.4 mmol) was then added, and after an additional 5minutes, 2N aqueous hydrochloric acid (3 mL) was added. The flask wasremoved from the bath and the yellow solution was partitioned betweenethyl acetate (30 mL) and water (30 mL). The ethyl acetate layer waswashed with saturated aqueous sodium chloride (20 mL), dried overmagnesium sulfate, filtered, and evaporated. The residual oil waspurified on preparative silica gel plates (3×1000 micron/ developed andeluted with 5% methanol/methylene chloride) to give the title compoundas a red solid (0.035 g).

¹H NMR (CDCl₃) d 7.09 (d, ArH), 7.78 (dd, ArH), 8.12 (d, ArH), 8.30(d,ArH), 8.70 (d, ArH) and 10.5 (s, CHO).

Step 6: 4-Hydroxymethyl-1,8-naphthosultam

A solution of 4-formyl-1,8-naphthosultam (0.035 g, 0.15 mmol) inanhydrous methanol (1 mL) was cooled in an ice bath under nitrogen.Sodium borohydride (0.011 g, 0.3 mmol) was added and the solution wasstirred for 30 minutes. The mixture was partitioned between methylenechloride (10 mL) and 0.2N aqueous hydrochloric acid (10 mL). The aqueouslayer was extracted with 5% methanol in methylene chloride (2×10 mL),and the combined organic layers were evaporated to give the titlecompound as a yellow solid (0.032 g).

¹H NMR (0.14mL CDCl₃ and 0.01 mL CD₃OD) d 5.13 (s, CH ₂OH), 6.85 (d,ArH), 7.50 (dd, ArH), 7.57 (d, ArH), 7.82 (d, ArH) and 7.88 (d, ArH).

Step 7: 4-(Triethylsilyloxy-methyl)-1,8-naphthosultam

A mixture of 4-hydroxymethyl-1,8-naphthosultam (2.92 g, 8.7 mmol),imidazole (0.74 g, 10.9 mmol), and triethylsilyl chloride (1.68 mL, 10.0mmol) in dichloromethane (40 mL) was stirred at room temperature under anitrogen atmosphere for 30 minutes. The reaction mixture was then washedwith 0.1 N HCl (80 mL), water (40 mL), and brine (40 mL), then driedover MgSO₄ and concentrated to a brown oil. The oil was stored at 0° C.for 72 hours. The crude product was purified by flash chromatography onEM silica gel 60 (5×15 cm) eluting with 4:1 hexane-ethyl acetate (200mL) followed by 2:1 hexane-ethyl acetate (1000 mL). Theproduct-containing fractions were combined and concentrated to give alight brown solid (2.3 g). The product was further purified byrecrystallization from 15:1 hexane-ethyl acetate (80 mL) to give thetitle compound (1.48 g) as large white needles. The mother liquor wasconcentrated and washed with cold hexane (10 mL) to provide additionaltitle compound (0.50 g) as smaller white needles.

¹H NMR (CDCl₃) d 0.73 (q, SiCH ₂CH₃), 1.03 (t, SiCH₂CH ₃), 5.26 (s,ArCH₂), 6.92 (d, ArH-7), 7.53 (dd, ArH-6), 7.59 (d, ArH-5), 7.93 and7.96 (two d's, ArH-2 and ArH-3)

Preparative Example 6 SYNTHESIS OF ALLYL(1S,5R,6S)-6-[(1R)-(ALLYLOXYCARBONYLOXY)-ETHYL]-1-METHYL-2-[4-(IODOMETHYL)-1,8-NAPHTHOSULTAMYL-METHYL]-CARBAPEN-EM-3-CARBOXYLATE

Step 1: Allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-[1(R)-methyl-2-oxo-3-[4-(2-triethylsilanyloxy-methyl)-1,8-naphthosultamyl]-propyl}-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate

A solution of allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-[3-hydroxy-1(R)-methyl-2-oxo-propyl]-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate(2.76 g, 4.3 mmol), 4-(2-triethylsilanyloxy-methyl)-1,8-naphthosultam(1.38 g, 3.9 mmol), and triphenylphosphine (1.53 g, 5.9 mmol) inanhydrous THF (20 mL) was placed under a nitrogen atmosphere and cooledin an ice bath. Diisopropyl azodicarboxylate (1.2 mL, 5.9 mmol) wasadded over one minute. The resulting orange solution was stirred at 0°C. for 30 minutes and then an additional 30 minutes at room temperature,after which the reaction mixture wad partitioned between ethyl acetate(80 mL) and brine (80 mL). The organic phase then dried over MgSO₄ andconcentrated. The concentrated solution was stored at 0° C. for 17hours. The crude product was purified by flash chromatography on EMsilica gel 60 (5×15 cm), eluting with 7:3 hexane-ethyl acetate (200 mL)followed by 1:1 hexane-ethyl acetate (1000 mL). The product-containingfractions were combined and concentrated to yield the title compound(3.2 g) as an off-white foam.

Step 2: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-[4-(2-triethylsilanyloxy-methyl)-1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate

A solution of allyl{3-[1(R)-(allyloxycarbonyloxy)-ethyl]-2-{1(R)-methyl-2-oxo-3-[4-(2-triethylsilanyloxy-methyl)-1,8-naphthosultamyl]-propyl}-(2R,3S)-4-oxo-azetidin-1-yl}-(triphenylphosphoranylidene)-acetate(3.2 g, 3.3 mmol) in anhydrous toluene (40 mL) was placed under anitrogen atmoshere and heated at reflux for 2.75 hours. The reactionmixture was allowed to cool to ˜40° C. and then concentrated to anorange oil. The oil was dissolved in dichloromethane (3 mL) and thenstored at 0° C. for 17 hours. The crude product was purified by flashchromatography on EM silica gel 60 (5×15 cm) eluting with 4:1hexane-ethyl acetate (400 mL) followed by 2:1 hexane-ethyl acetate (850mL). The product-containing fractions were concentrated to give thetitle compound (1.6 g) as an off-white foam.

¹H NMR (CDCl₃) d 0.73 (q, SiCH ₂CH₃), 1.02 (t, SiCH₂CH ₃), 1.31 (d,1-CH₃), 1.45 (d, CH₃ CHO), 3.40 (dq, H-1), 3.44 (dd, H-6), 4.16 (dd,H-5), 4.59 (m, OCO₂CH₂), 4.67 (d, 2-CHaHb), 4.88 (m, CO₂CH₂), 5.13 (dq,CH₃CHO), 5.26 (m, ArCH₂O and 1 vinyl-H), 5.32-5.36 (m, 2 vinyl-H's),5.40 (d, CHaHb) 5.50-5.54 (m, vinyl-H), 5.86-5.96 (m, vinyl-H),6.00-6.10 (m, vinyl-H), 6.72 (dd, Ar H-7), 7.52 (m, Ar H5 and Ar H6),7.94 and 7.98 (two d's, Ar H₂ and Ar H3)

Step 3: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[4-(hydroxymethyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2em-3-carboxylate

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-[4-(2-triethylsilanyloxy-methyl)-1,8-naphthosultamyl-methyl]-carbapen-2-em-3-carboxylate(1.50 g, 2.15 mmol) in tetrahydrofuran (32 mL) was diluted with water(16 mL) and treated with 1N aqueous triflouromethanesulfonic acid (301mL, 0.301 mmol). After stirring at room temperature for 20 minutes thereaction mixture was partitioned between dichloromethane (200 mL) and 5%aqueous bicarbonate (60 mL). The aqueous phase was extracted withdichloromethane (30 mL) and the combined organic phase was concentratedto yield the title compound (1.56 g) as a white foam.

Step 4: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[4-(iodomethyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2-em-3-carboxylate

Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[4-(hydroxymethyl)-1,8-naphthosultamyl-methyl]-1-methyl-carbapen-2-em-3-carboxylatewas dissolved in dichloromethane (49 mL) and cooled in an ice bath underan atmosphere of nitrogen. Triethylamine (0.524 mL, 3.8 mmol) followedby methanesulfonyl chloride (0.258 mL, 3.23 mmol) was added and thereaction mixture was allowed to stir at 2° C. for 40 minutes. Thereaction mixture was then partitioned between dichloromethane (250 mL)and 0.1 N aqueous HCl (200 mL), and the organic phase dried over MgSO₄then concentrated and dried under vacuum for 20 hours. The resultingmesylate (1.7 g, quant.) was dissolved in acetone (60 mL) and sodiumiodide (1.95 g, 13 mmol) was added. This suspension was stirred for 80minutes at room temperature under a nitrogen atmosphere. The reactionmixture was then partitioned between dichioromethane (200 mL) and water(200 mL). The aqueous phase was extracted with dichloromethane (50 mL)and the combined organic phase was washed with 5% NaHSO₃ (2×75 mL),dried over MgSO₄ and then concentrated. The resulting yellow oil waslyophilized from benzene (40 mL) to afford the title compound (1.5 g,quant.) as an amorphous yellow solid.

¹H NMR (CDCl₃) 1.28 (d, 1-CH₃), 1.42(d, CH₃ CHO), 3.36 (dq, H-1), 3.42(dd, H-6), 4.13 (dd, H-5), 4.42-4.68 (m, OCO₂CH₂), 4.63 (d, 2-CHaHb),4.76-4.94 (m, CO₂CH₂), 5.10 (dq, CH ³ CHO), 5.20-5.34 (m, 3 vinyl-H),5.38 (d, ArCH₂I), 5.38 (d, CHHb), 5.49 (m, vinyl-H), 5.80-5.90 (m,vinyl-H), 5.94-6.06 (m, vinyl-H), 6.72 (dd, Ar H-7), 7.60-7.64 (m, Ar H5and Ar H6), 7.77 and 7.84 (two d's, Ar H2 and Ar H3)

Preparative Example 7 SYNTHESIS OF3-AZIDO-1(1,4-DIMETHYL-PIPERAZINIUM)-PROPANE TRIFLUOROMETHANESULFONATE

Step 1: 1-Azido-3-chloropropane

Sodium azide (1.43 g, 22 mmol) and lithium chloride (0.93 g, 22 mmol)are added to DMF (10 ml) under nitrogen. To this was added1,3-bromochloropropane (3.14g, 2.0 ml, 20 mmol) and the reaction mixtureis stirred and heated at 50° for 5 hours. The reaction mixture wasdiluted with water and extracted with petroleum ether. The organic phasewas washed twice with water, dried over MgSO₄ and evaporated to give1,3-azidochloropropane.

Step 2: 3-Azido-1(1.4-dimethyl-piperazinium)-propanetrifluoromethanesulfonate.

The azidochloropropane from Step 1 is dissolved in acetonitrile (8 ml)and treated with 1,4-dimethylpiperazine (1.12 g, 10 mmol). Sodium iodide(0.15 g, 1 mmol) is added and the reaction is stirred under nitrogen at50° for 6 hr. The solvent is removed under reduced pressure and theresidue is triturated with ether, the ether solution is decanted off andthe residue is taken up in acetonitrile (10 ml) and treated with silvertrifluoromethane sulfonate (2.56 g, 10 mmol). After 10 min. theprecipitated silver salts are filtered through a bed of celite andwashed with a little acetonitrile. The filtrate and washings areevaporated to give the crude product which is crystallized fromEtOH/Et₂O to give the product.

Following the above procedure and starting with the appropriatechlorobromoalkane one obtains the following compounds of PreparativeExamples 8 to 10.

Preparative Example 8 2-AZIDO-1(1,4-DIMETHYL-PIPERAZINIUM)-ETHANETRIFLUOROMETHANESULFONATE

Preparative Example 9 4-AZIDO-1(1,4-DIMETHYL-PIPERAZINIUM)-BUTANETRIFLUOROMETHANESULFONATE

Preparative Example 10 5-AZIDO-1( 1,4-DIMETHYL-PIPERAZINIUM)-PENTANETRIFLUOROMETHANESULFONATE

Preparative Example 11 3-AZIDO-1(1,4-DIMETHYL-PIPERAZINIUM)-BUTANETRIFLUOROMETHANESULFONATE

Step 1: 3-Bromo-1(1.4-dimethyl-piperazinium)-butane bromide

1,3-Dibromobutane (2.15 g, 1.2 ml, 10 mmol) is dissolved in acetonitrile(2 ml). DABCO (1.23 g, 11 mmol) is added. The reaction mixture is heatedat 65° under nitrogen for 2 hr. The acetonitrile is removed underreduced pressure to give the product.

Step 2: 3-Azido-1( 1.4-dimethyl-piperazinium)-)-butanetrifluoromethanesulfonate

The product from Step 1 is dissolved in DMF (5 ml). Sodium azide (0.71g, 11 mmol) and lithium chloride (0.5 g, 11 mmol) are added followed bysodium iodide (0.149 g, 1 mmol). The reaction is stirred at 50°, undernitrogen overnight. The DMF is removed under reduced pressure with anexternal bath temperature of 40°. The residue is taken up inacetonitrile (5 ml) and methanol (5 ml) and treated with silver triflate(2.8 g, 11 mmol). After 0.5 hr the precipitated silver salts arefiltered off through a bed of celite and washed with a little methanol.The filtrate and washings are evaporated to give an oil. Triturationwith ether gives the product.

Preparative Example 12N-(4-AZIDOMETHYLPHENYL)-1-(1.4-DIMETHYL-PIPERAZINIUM)ACETAMIDE TRIFLATE

Step 1: N-(4-Hydroxymethylphenyl)chloroacetamide

A solution of 4-aminobenzyl alcohol (2 g, 16.3 mmol), pyridine (1.3 mL,16.3 mmol) in CH₂Cl₂ (50 mL) is treated with chloroacetochloride (1.29mL, 16.2 mmol) at 0° C. The mixture is stirred for 0.5 hr and thenwashed with water, 1N HCl, water and brine. It is dried over Na₂SO₄ andconcentrated. The residue is chromatographed over silica gel (eluent:hexane:ethyl acetate v/v 2:1) to give the product (0.54 g) as a whitesolid.

Step 2: 4-(1-Chloroacetamido)benzyl methanesolfonate

A solution of N-(4-hydroxymethylphenyl)chloroacetamide (0.25 g, 1.25mmol), Et₃N (0.5 mL, 3.46 mmol), solvent CH₂Cl₂ (30 mL) and THF (10 mL)is treated with methanesulfonyl chloride (0.1 mL, 1.29 mmol) at 0° C.The mixture is kept at 0° C. for 0.5 hr and more CH₂Cl₂ is added. It isthen washed with water and brine, dried over Na₂SO₄ and concentrated togive the product (0.313 g).

Step 3: N-(4-Azidomethylphenyl)chloroacetamide

A mixture of 4-(1-chloroacetamido)benzyl methanesolfonate (0.313 g, 1.13mmol), sodium azide (73 mg, 1.13 mmol), lithium chloride (48 mg, 1.13mmol), DMF (10 mL) and catalytic amount of sodium iodide is stirred atroom temperature for 3 days. Most of the DMF is then removed undervacuum. The residue is taken up in ethyl acetate and washed with water 3times. The organic layer is dried over Na₂SO₄ and concentrated. Theresidue is chromatographed over silica gel (eluent: Hexane:ethyl acetatev/v 2:1) to give the product (77 mg) as a white solid.

Step 4: N-(4-azidomethylphenyl)-1-(1,4-dimethyl-piperazinium)acetamidetriflate

A solution of N-(4-azidomethylphenyl)chloroacetamide (77 mg, 0.343mmol), 1,4-dimethylpiperazine (35 mg, 0.313 mmol) and CH₃CN (3 mL) isstirred at room temperature for 3 days. The solent is removed and theresidue is dried under vacuum to give the product (0.115 g) as chloride.This chloride is dissolved in MeOH (3 mL) and treated with a solution ofAgOTf (80 mg, 0.31 mmol) in CH₃CN (0.5 mL). The mixture is stirred for0.5 hr, then filtered to remove the white precipitate. The filter cakeis washed with CH₃CN. The combined filtrate is concentrated to give theproduct as a triflate salt.

Preparative Example 13N-(4-(2-(ALLYLOXYCARBONYLAMINO)ETHYL)PHENYL)-1-(1,4-DIMETHYL-PIPERAZINIUM)ACETAMIDETRIFLATE

Step 1:N-(4-aminophenethyl-O-allyl carbamate

To a solution of 4-aminophenethyl amine (2 g, 14.7 mmol) in CH₂Cl₂ (20mL) is added allyl chloroformate (0.533 mL, 4.89 mmol) at 0° C. Themixture is kept at 0° C. for 0.5 hr and more CH₂Cl₂ is added. It is thenwashed with 5% NaHCO₃, water and brine, dried over Na₂SO₄ andconcentrated. The residue is chromatographed over silica gel (eluent:ethyl acetate:hexane v/v 1:1) to give the product (1.38 g) as a whitesolid.

Step 2: N-(4-(2-(Allyloxycarbonylamino)ethyl)phenyl)chloroacetamide

A solution of N-(4-aminophenethyl)-O-allyl carbamate (1.38 g, 6.28mmol), Et₃N (1.5 mL, 10.4 mmol) in CH₂Cl₂ (30 mL) is treated withchloroacetochloride (0.52 mL, 6.53 mmol) at 0° C. The mixture is stirredfor 20 min and then washed with water, 1N HCl, water and brine. It isdried over Na₂SO₄ and concentrated to give the product (1.58) as a whitesolid.

Step3:N-(4-(2-(Allyloxycarbonylamino)ethyl)phenyl)-1-(1,4-dimethyl-piperazinium)acetamidetriflate

A solution ofN-(4-(2-(allyloxycarbonylamino)ethyl)phenyl)chloroacetamide (0.5 g, 1.68mmol), 1,4-dimethylpiperazine (0.18 g, 1.61 mmol) and CH₃CN (10 mL) isstirred at room temperature overnight. The solid is collected byfiltration and dried under vacuum to give the white crystal product aschloride.

This chloride is dissolved in MeOH (10 mL) and treated with a solutionof AgOTf (0.31 g, 1.21 mmol) in CH₃CN (2 mL). The mixture is stirred for0.5 hr, then filtered to remove the white precipitate. The filter cakeis washed with CH₃CN. The combined filtrate is concentrated to give theproduct as a triflate salt.

Preparative Example 14N-(2-ALLYLOXYCARBONYLAMINO)ETHYL)-1-(1,4-DIMETHYL-PIPERAZINIUM)ACETAMIDETRIFLATE

Step 1: N-(2-aminoethyl)-O-allyl carbamate

Ethelene diamine (1.8 g, 30 mmol) is dissolved in water (5.8 mL) with 5drops of bromocresol green indicator. Methanesulfonyl chloride (c=0.92g/mL H₂O) is added until the solution turned to pale yellow (pH˜3.8).The solution is diluted with EtOH (16 mL), vigorously stirred, andtreated simutaneously with solutions of allylchloroformate (3.61 g, 30mmol) in dimethoxyethane (5.8 mL) and potassium acetate (c=50% w/v H₂O)by alternate dropwise additions to maintain the pale yellow-greencolouration of the indicator. After the additions are complete themixture is stirred for 1 hr and the volatiles are removed under vacuum.The residue is shaken with warter and filtered to remove smallquantities of the bis-derivative. The filtrate is washed with benzene,basified with excess 40% aqueous NaOH, and then extracted with benzene.The organic layer is washed with brine, dried over Na₂SO₄ andconcentrated to give the product (0.6 g) as a yellow oil.

Step 2: N-(2-Allyloxycarbonylaminoethyl)chloroacetamide

A solution of N-(2-aminoethyl)-O-allyl carbamate (0.6 g,4.17 mmol), Et₃N(1.0 mL, 6.93 mmol) in CH₂Cl₂ (20 mL) is treated withchloroacetochloride (0.35 mL, 4.17 mmol) at 0° C. The mixture is stirredfor 20 min and then washed with water, 1NHCl, water and brine. It isdried over Na2SO₄ and concentrated to give the product (0.474 g) as ablack solid.

Step3:N-(2-Allyloxycarbonylamino)ethyl)-1-(1,4-dimethyl-piperazinium)acetamidetriflate

A solution of N-(2-allyloxycarbonylaminoethyl)chloroacetamide (0.47 g,2.13 mmol), 1,4-dimethylpiperazine (0.167 g, 1.5 mmol) and CH₃CN (20 mL)is stirred at room temperature for 3 days. The solvent is removed andthe residue is dried under vacuum to give the product as the chloride.This chloride is dissolved in MeOH (10 mL) and treated with a solutionof AgOTf (0.38 g, 1.48 mmol) in CH₃CN (2 mL). The mixture is stirred for0.5 hr, then filtered to remove the precipitate. The filter cake iswashed with CH₃CN. The combined filtrate is concentrated to give theproduct as a triflate salt.

Preparative Example 15N-((3-ALLYLOXYCARBONYLAMINO)PROPYL)-1-(1,4-DIMETHYL-PIPERAZINIUM)ACETAMIDETRIFLATE

Following the procedure described in Preparative Example 14, step 1 tostep 3 and starting from 1,3-propanediamine, the title compound isobtained.

Preparative Example 16N-(3-(2-ALLYLOXYCARBONYLAMINO)ETHYL)PHENYL)-1-(1,4-DIMETHYL-PIPERAZINIUM)ACETAMIDETRIFLATE

Step 1:3-Nitrophenethyl azide

To a solution of 3-nitrophenethyl alcohol (2 g, 11.97 mmol), Et₃N (3.0mL, 20.8 mmol) in CH₂Cl₂ (40 mL) is added methanesulfonyl chloride (1.0mL, 12.9 mmol) at 0° C. After stirring for 0.5 hr, more CH₂Cl₂ is added.The solution is washed with water and brine, dried over Na₂SO₄ andconcentrated. The residue is dissolved in DMF (30 mL), sodium azide (0.8g,12.3 mmol), lithium chloride (0.53 g, 12.5 mmol) and catalytic amountof sodium iodide are added. The mixture is stirred at room temperatureovernight. Most of DMF is then removed under vacuum and the residue iswashed with water and brine, dried over Na₂SO₄ and concentrated. Theresidue is chromatographed over silica gel (eluent: hexane:ethyl acetatev/v 4:1) to give a pale yellow oil (1.8 g) as desired product.

Step 2:3-Nitrophenethylamine

A mixture of 3-nitrophenethyl azide (0.9 g, 4.69 mmol), triphenylphosphine (1.22 g, 4.66 mmol) and CH₂Cl₂ (80 mL) is stirred at roomtemperature for 3 days. Solvent is removed and the residue is taken upin EtOH (20 mL). The solution is heated to 70° C., added 2M NaOH aqueoussolution (10 mL) and stirred at room temperature for 2 hrs. A 10% HClaqueous solution (20 mL) is then added and refluxed for 2 hrs. After themixture cool to room temperature, it is washed with benzene, basifiedwith 5N NaOH to pH˜12, extracted with ethyl acetate. The organic layeris dried over Na₂SO₄ and concentrated to give the product (0.63 g) as ayellow oil.

Step 3: N-(2-(3-Nitrophenyl)ethyl)-O-allyl carbamate

To a solution of 3-nitrophenylamine (0.62 g, 3.73 mmol) and Et₃N (0.8mL, 5.54 mmol) in CH₂Cl₂ (20 mL) is added allyl chloroformate (0.4 mL,3.77 mmol) at 0° C. The mixture is kept at 0° C. for 0.5 hr and moreCH₂Cl₂ is added. It is then washed with 5% NaHCO₃, water and brine,dried over Na₂SO₄ and concentrated to give the product (0.9 g).

Step 4: N-(2-(3-Aminophenyl)ethyl)-O-allyl carbamate

A mixture of N-(2-(3-Aminophenyl)ethyl)-O-allyl carbamate (0.9 g, 3.6mmol), tin(II) chloride dihydrate (4.1 g, 18 mmol) in EtOH (50 mL) isheated at 70° C. for 1 hr. The EtOH is removed and the residue is addedwater, basified with 5N NaOH to pH>10, extrated with CH₂Cl₂. The organiclayer is washed with water and brine, dried over Na₂SO₄, concentrated togive the product (0.66 g).

Step 5: N-((3-(2-allyloxycarbonylamino)ethyl)phenyl)chloroacetamide

A solution of N-(2-(3-Aminophenyl)ethyl)-O-allyl carbamate (0.66 g,3.0mmol), Et₃N (0.65 mL, 4.5 mmol) in CH₂Cl₂ (20 mL) is treated withchloroacetochloride (0.26 mL, 3.2 mmol) at 0° C. The mixture is stirredfor 20 min and then washed with water, 1NHCl, water and brine. It isdried over Na₂SO₄ and concentrated to give the product (0.62 g).

Step 6:N-(3-(2-Allyloxycarbonylamino)ethyl)phenyl)-1-(1.4-dimethyl-piperazinium)acetamidetriflate

A solution ofN-((3-(2-allyloxycarbonylamino)ethyl)phenyl)chloroacetamide (0.32 g,1.08 mmol), 1,4-dimethylpiperazine (0.121 g, 1.08 mmol) and CH₃CN (10mL) is stirred at room temperature overnight. The solvent is removed andthe residue is dried under vacuum to give the product as chloride. Thischloride is dissolved in MeOH (10 mL) and treated with a solution ofAgOTf (0.27 g, 1.08 mmol) in CH₃CN (1 mL). The mixture is stirred for0.5 hr, then filtered to remove the white precipitate. The filter cakeis washed with CH₃CN. The combined filtrate is concentrated to give theproduct as a triflate salt.

Preparative Example 17N-(2-(2-ALLYLOXYCARBONYLAMINO)ETHYL)PHENYL)-1-(1,4-DIMETHYL-PIPERAZINIUM)ACETAMIDETRIFLATE

Following the procedure described in Example 16, step 1 to step 6starting from 2-nitrophenethyl alcohol, the title compound is obtained.

Preparative Example 18(S)-(−)-3-AZIDO-1-(1,4-DIMETHYL-PIPERAZINIUM)-2-METHYLPROPANE TRIFLATE

Step 1: (R)-(−)-3-azido-2-methylpropanol

A mixture of (R)-(−)-3-bromo-2-methylpropanol (1 g, 6.53 mmol), sodiumazide (0.47 g, 7.23 mmol), lithium chloride (0.31 g, 7.29 mmol) and DMF(10 mL) is heated at 50° C. overnight. Most of DMF is then removed. Theresidue is taken up in ethyl acetate, washed with water and brine, driedover Na₂SO₄ and concentrated to give the product (0.64 g).

Step 2: (S)-(−)-3-Azido-1-(1,4-dimethyl-piperazinium)-2-methylpropanetriflate

(R)-(−)-3-azido-2-methylpropanol (0.64 g, 5.56 mmol) is dissolved inCH₂Cl₂ (40 mL). 2,6-lutidine (1.9 mL, 16.3 mmol) is added at −20° C.followed by adding trifalic anhydride (1,4 mL, 8.32 mmol). The mixtureis kept in −20° C. for 40 min, diluted with CH₂Cl₂ washed with water,0.1 N HCl aqueous solution, water and brine, dried over Na₂SO₄ andconcentrated to give the trifalte (1.33 g). The triflate (0.7 g, 2.83mmol) is reacted with 1,4-dimethylpiperazine (0.31 g, 2.77 mmol) inCH₃CN for 3 hrs. The solvent is removed and the residue is dried undervacuum to give the product.

EXAMPLE 1

(1S,5R,6S)--2-{6-[2-(4-(3-AMMONIOPROPYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL]-1,1-DIOXO-2-H-1-THIA-2-AZA-ACENAPHTHALEN-2-YL-METHYL}-6-[1(R)-HYDROXYETHYL]-1-METHYL-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Step 1: Allyl(1S,5R,6S)--6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-{6-[2-(4-(3-azidopropyl)-1,4-dimethyl-piperazin-1-io]-ethyl-1,1-dioxo-2-H-1-thia-2-aza-acenaphthalen-2-yl-methyl}-1-methyl-carbapen-2-em-3-carboxylatebis (trifluoromethanesulfonate)

Allyl(1S,5R,6S)--6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-[6-(2-trifluoromethanesulfonyloxyethyl)-ethyl]-1,1-dioxo-2H-1-thia-2-aza-acenaphthalen-2-yl-methyl}-1-methyl-carbapen-2-em-3-carboxylatefrom Step 4, Preparative Example 2, (150 mg,) is dissolved inacetonitrile (1.5 ml), 3-Azido-1(1,4-dimethyl-piperazinium)-propanetrifluoromethanesulfonate (85 mg,) from Step 2, Preparative Example 7,is added. The reaction is stirred 5 min. and the solvent is evaporatedunder vacuum to give a thick oil which is stirred at room temperaturefor 45 min. The residual solvent is removed to give the product which isused in the next step without purification.

Step 2:(1S,5R,6S)--2-{6-[2-(4-(3-ammoniopropyl)-1,4-dimethyl-piperazin-1-io)-ethyl]-1,1-dioxo-2-H-1-thia-2-aza-acenaphthalen-2-yl-methyl}-6-[1(R)-hydroxyethyl]-1-methyl-carbapen-2-em-3-carboxylatedichloride

Allyl(1S,5R,6S)--6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-{6-[2-(4-(3-ammoniopropyl)-1,4-dimethyl-piperazinium]-ethyl-1,1-dioxo-2H-1-thia-2-aza-acenaphthalen-2-yl-methyl}-1-methyl-carbapen-2-em-3-carboxylatebis (trifluoromethanesulfonate) from Step 1 is dissolved in DMF (1.5ml), Phenylsilane ( 115 ml) is added, followed bytetrakis(triphenylphosphine)palladium(0) (22.5 mg, 0.019 mmol). Thereaction is stirred at room temperature for 10 min. then diluted withether (5 ml) to precipitate the product. The ether solution is decantedoff and the residue washed with 2×7 ml ether. The combined ethersolutions are centrifuged and the precipitate combined with the originalprecipitate is dissolved in acetonitrile/water 1/1 (2 ml). This solutionis applied to a column of Macro-Prep CM weak cation exchange resin (5ml). The column is eluted with 1:1 acetonitrile-water (8 ml) followed bywater (10 ml). The resin is eluted with 5% aqueous sodium chloride (75ml) and collected in 5-15 ml fractions. The first four fractionscontaining the product are combined and treated with 5% rhodium oncarbon (50 mg) and stirred under an atmosphere of hydrogen. After 1 hourthe catalyst is filtered off and the filtrate is loaded onto a RaininMicrosorb C18 RP HPLC column (2×30 cm). Gradient elution withacetonitrile/0.12M aqueous ammonium chloride gives pure productcontaining fractions which are combined and concentrated under vacuum.The concentrated product is applied to a column of Amberchrome CG-161 4ml) which is eluted with water (10 ml) followed by 1:1acetonitrile-water (10 ml). The acetonitrile-water eluate is lyophilizedto give the product.

EXAMPLE 2(1S,5R,6S)--2-{6-[2-(4-(2-AMMONIOETHYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL]-1,1-DIOXO-2-H-1-THIA-2-AZA-ACENAPHTHALEN-2-YL-METHYL}-6-[1(R)-HYDROXYETHYL]-1-METHYL-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Substituting 2-Azido-1(1,4-dimethyl-piperazinium)-ethanetrifluoromethanesulfonate for3-Azido-1(1,4-dimethyl-piperazinium)-propane trifluoromethanesulfonatein Example 1, Step 1 above, and following the procedure of Step 2 oneobtains the desired product.

EXAMPLE 3(1S,5R,6S)-2-{6-[2-(4-(4-AMMONIOBUTYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL]1-1,1-DIOXO-2-H-1-THIA-2-AZA-ACENAPHTHALEN-2-YL-METHYL}-6-[1(R)-HYDROXYETHYL]-1-METHYL-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Substituting 4-Azido-1(1,4-dimethyl-piperazinium)-butanetrifluoromethanesulfonate for3-Azido-1(1,4-dimethyl-piperazinium)-propane trifluoromethanesulfonatein Example 1, Step 1 above, and following the procedure of Step 2 oneobtains the desired product.

EXAMPLE 4(1S,5R,6S)--2-{6-[2-(4-(5-AMMONIOPENTYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL]-1,1-DIOXO-2-H-1-THIA-2-AZA-ACENAPHTHALEN-2-YL-METHYL)-6-[1(R)-HYDROXYETHYL]-1-METHYL-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Substituting 5-Azido-1( 1,4-dimethyl-piperazinium)-pentanetrifluoromethanesulfonate for3-Azido-1(1,4-dimethyl-piperazinium)-propane trifluoromethanesulfonatein Example 1, Step 1 above, and following the procedure of Step 2, oneobtains the desired product.

EXAMPLE 5(1S,5R,6S)--2-{6-[2-(4-(3-AMMONIO-3-METHYLPROPYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL]-1,1-DIOXO-2-H-1-THIA-2-AZA-ACENAPHTHALEN-2-YL-METHYL)-6-[1(R)-HYDROXYETHYL]-1-METHYL-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Substituting 3-Azido-1(1,4-dimethyl-piperazinium)-butanetrifluoromethanesulfonate for3-Azido-1(1,4-dimethyl-piperazinium)-propane trifluoromethanesulfonatein Example 1, Step 1 above, and following the procedure of Step 2, oneobtains the desired product.

EXAMPLE 6(1S,5R,6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL2-{6-(2-(4-(3(R)-AMONIO-2-METHYLPROPYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-METHYL}CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Substituting 3-Azido-2-methyl-1(1,4-dimethyl-piperazinium)-propanetrifluoromethanesulfonate for3-Azido-1(1,4-dimethyl-piperazinium)-propane trifluoromethanesulfonatein Example 1, Step 1, and following the procedure of Step 2, one obtainsthe desired product.

EXAMPLE 7(1S,5R,6S)--2-{6-[2-(4-(3-METHYLAMMONIOPROPYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL]-1,1-DIOXO-2-H-1-THIA-2-AZA-ACENAPHTHALEN-2-YL-METHYL}-6-[1(R)-HYDROXYETHYL]-1-METHYL-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Starting with allylN-[3-(1,4-dimethylpiperazinium)propyl]-N-methylcarbamatetrifluoromethanesulfonate and the product of Preparative Example 2, andfollowing the procedure of steps 1 and 2 of Example 11, one obtains thetitle compound.

EXAMPLE 8(1S,5R,6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL-2-{6-(2-(4-(3-AMONIOPROPYL)AMINOCARBONYLMETHYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-METHYL}CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Substituting the products of Preparative Examples 2 and 15, in step 1 ofExample 11, followed by step 2 of Example 11, provides the titlecompound.

EXAMPLE 9(1S,5R,6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL-2-}6-(2-(4-(2-AMONIOETHYL)AMINOCARBONYLMETHYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-METHYL}CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Substituting the product of Preparative Examples 2 and 14 in step 1 ofExample 11 followed by Step 2 of Example 11 provides the title compound.

EXAMPLE 10 SYNTHESIS OF(1S,5R,6S)-2-3-{2-[4-(3-AMMONIO-PROPYL)-1-DIMETHYL-PIPERAZIN-1-IO)-ETHYL}-1,8-NAPHTHOSULTAMYL-METHYL)-6-[(1R)-HYDROXY-ETHYL]-1-METHYL-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Step 1: Allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl}-2-(3-{2-[4-(3-azido-propyl)-1,4-dimethyl-piperazin-1-io]-ethyl-1,8-naphthosultamyl-methyl)-1-methyl-carbapen-2-em-3-carboxylatebis(trifluoromethanesulfonate)

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-(3-[2-(trifluoromethanesulfonyloxy)-ethyl]-1,8-naphthosultamyl-methyl}-carbapen-2-em-3-carboxylate(0.141 mmol) in anhydrous acetonitrile (1.0 mL) is added to1-(3-azido-propyl)-1,4-dimethylpiperazinium trifluoromethanesulfonate(51 mg, 0.144 mmol). The solution is concentrated under vacuum toapproximately 0.2 mL and let stand at room temperature for 2 hours. Theoil is triturated with diethyl ether, the solvent decanted, and theresidue dried under vacuum to afford the title compound as an amorphoussolid. It is used in the next step without further purification.

Step 2:(1S,5R,6S)-2-(3-{2-[4-(3-Ammonio-propyl)-1,4-dimethyl-piperazin-1-io]-ethyl}-1,8-naphthosultamyl-methyl)-6-[(1R)-hydroxy-ethyl]-1-methyl-carbapen-2-em-3-carboxylatedichloride

A solution of crude allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-2-(3-{2-[4-(3-azido-propyl)-1,4-dimethylpiperazin-1-io]-ethyl}-1,8-naphthosultamyl-methyl)-1-methyl-carbapen-2-em-3-carboxylatebis(trifluoromethanesulfonate) (0.141 mmol) in anhydrousdimethylformamide (1,4 mL) is treated with5,5-dimethyl-1,3-cyclohexanedione (dimedone, 59 mg, 0.423 mmol),triphenylphosphine (5.5 mg, 0.021 mmol) andtetrakis(triphenylphosphine)palladium(0) (8.1 mg, 0.007 mmol). Themixture is placed under a nitrogen atmosphere, treated withN,N-diisopropylethylamine (0.074 mL, 0.423 mmol), and stirred at roomtemperature. After 20 minutes, the mixture is added to diethyl ether (13mL) and centrifuged. The supernatant is decanted from the orange coloredsolid which is washed with more ether (14 mL) and dried under vacuum toafford crude(1S,5R,6S)-2-(3-{2-[4-(3-azido-propyl)-1,4-dimethylpiperazin-1-io]-ethyl)-1,8-naphthosultamyl-methyl)-6-[(1R)-hydroxy-ethyl]-1-methyl-carbapen-2-em-3-carboxylatetrifluromethanesulfonate.

The deallylated product is dissolved in tetrahydrofuran (2 mL), water (4mL) and ethanol (3 mL), treated with 5% rhodium on carbon (17 mg), andstirred under an atmosphere of hydrogen. After 65 minutes, the mixtureis filtered and the filtrate applied to a column of Macro-Prep CM weakcation exchange resin (3 mL). The column is eluted with 1:1acetonitrile-water (10 mL), water (12 mL), and 5% aqueous sodiumchloride (40 mL). The saline fractions are concentrated under vacuum to9 mL and loaded onto a Ranin Microsorb C₁₈ RP HPLC column (2×30 cm)which is gradiently eluted with acetonitrile in 0.12M aqueous ammoniumchloride. The product containing fractions are concentrated under vacuumthen applied to a column of Amberchrom CG161 which is eluted with water(25 mL) followed by 20% isopropanol in water. The product eluted sharplywith isopropanol-water. The product containing fractions diluted withwater, concentrated under vacuum to 4 mL, and lyophilized to afford thetitle compound.

EXAMPLE 11 SYNTHESIS OF(1S,5R,6S)-6-[(1R)-HYDROXY-ETHYL]-1-METHYL-2-(3-{2-[4-(3-METHYLAMMONIO-PROPYL)-1,4-DIMETHYL-PIPERAZIN-1-IO]-ETHYL}-1,8-NAPHTHOSULTAMYL-METHYL)-CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Step 1:Allyl(1S,5R,6S)-2-[3-(2-{4-[4-(allyloxycarbonyl]-4-aza-pent-1-yl]-1,4-dimethyl-piperazin-1-io}-ethyl)-1,8-naphthosultamyl-methyl]-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-carbapen-2-em-3-carboxylatebis(trifluoromethanesulfonate)

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{3-[3-(trifluoromethanesulfonyloxy)-propyl]-1,8-naphthosultamyl-methyl}-carbapen-2-em-3-carboxylate(0.172 mmol) in anhydrous acetonitrile (0.9 mL) is treated with allylN-[3-(1,4-dimethylpiperazinium)-propyl]-N-methyl-carbamatetrifluoromethanesulfonate (76 mg, 0.188 mmol). The solution kept at roomtemperature for one hour then stored in a freezer at −10° C. for 3.5days. The solvent is evaporated under vacuum. The residual oil istriturated with diethyl ether, the solvent decanted, and the residuedried under vacuum to afford the title compound as an amorphous solid.It is used in the next step without further purification.

Step 2:(1S,5R,6S)-6-[(1R)-Hydroxy-ethyl]-1-methyl-2-(3-{2-[4-(3-methylammonio-propyl)-1,4-dimethyl-piperazin-1-io]-ethyl}-1,8-naphthosultamyl-methyl)-carbapenem-2-em-3-carboxylatedichloride

A solution of crude allyl(1S,5R,6S)-2-[3-(2-(4-[4-(allyloxycarbonyl]-4-aza-pent-1-yl]-1,4-dimethylpiperazin-1-io}-ethyl)-1,8-naphthosultamyl-methyl]-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-carbapen-2-em-3-carboxylatebis(trifluoromethanesulfonate) (0.172 mmol) andtetrakis(triphenylphosphine)palladium(0) (10.0 mg, 0.086 mmol) inanhydrous dimethylformamide (0.86 mL) is placed under a nitrogenatmosphere and treated with phenylsilane (0.191 mL, 1.55 mmol). Afterstirring for 20 minutes at room temperature, the dark solution is addedto diethyl ether (12 mL) to give a brown precipitate. The supernatant isdecanted and the residue dried under vacuum to give a solid (246 mg).

The solid is dissolved in 1:1 acetonitrile-water (3 mL) and applied to acolumn of Macro-Prep CM weak cation exchange resin (4 mL). The column iseluted with 1:1 acetonitrile-water (7 mL), water (18 mL), 5% aqueousNaCl (9 mL), and 1:1 isopropanol-10% aqueous NaCl (10 mL). The productcontaining fractions (5% NaCl and 1:1 iPrOH-10% NaCl) wre combined andconcentrated under vacuum to remove isopropanol. The resulting solutionis applied to a column of Amberchrom CG-161 resin (5 mL) which is elutedwith water (20 mL) followed by 20% isopropanol in water (6 mL). Theproduct containing fractions (20% iPrOH) are concentrated under vacuum,diluted with water, reconcentrated, filtered, and lyophilized to give apale yellow, amorphous solid (43 mg, 35% yield). This material isfurther purified by HPLC on a Ranin Microsorb C₁₈ RP column (2×30 cm)which is gradiently eluted with acetonitrile (0-30%) in 0.12M aqueousammonium chloride. The product containing fractions (30% MeCN in 0.12MNH4Cl) are desalted on Amberchrom CG-161 (5 mL) as described above andthe final aqueous solution lyophilized to provide the title compound asan amorphous, white solid.

EXAMPLE 12(1S,5R,6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL-2-{6-(2-(4-(4-AMONIOMETHYLPHENYL)AMINOCARBONYL)METHYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-METHYL}CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Step 1: Allyl(1S,5R,6S)--6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{6-(2-(4-(4-azidomethylphenyl)aminocarbonyl)methyl)-1,4-dimethyl-piperazin-1-io)-ethyl)-1,1-dioxo-1H-1-thia-2-aza-acenaphthylen-2-yl-methyl}carbapen-2-em-3-carboxylatebis-trifluormethylsulfonate

Starting withN-(4-azidomethylphenyl)-1-(1,4-dimethylpiperazinium)acetamide triflate(18.5 mg) from Preparative Example 12 and reacting it with the productof Step 4, Preparative Example 2, according to the procedure of Example1, step 1, one obtains the title product, which is used in the next stepwithout further purification.

Step 2.(1S,5R,6S)-6-(1(R)-hydroxy=-ethyl)-1-methyl-2-{6-(2-(4-(4-amoniomethylphenyl)aminocarbonyl)methyl)-1,4-dimethyl-piperazin-1-io)-ethyl)-1,1-dioxo-1H-1-thia-2-aza-acenaphthylen-2-yl-methyl}carbapen-2-em-3-carboxylatedichloride

The product from Step 1 is dissolved in DMF (0.2 ml), Phenylsilane ( 30ml) is added, followed by tetrakis(triphenylphosphine)palladium(0) (2mg). The reaction is stirred at room temperature for 15 min. thendiluted with ether (2 ml) to precipitate the product. The ether solutionis decanted off and the residue washed with 2×2 ml ether. The combinedether solutions are centrifuged and the precipitate combined with theoriginal precipitate is dissolved in acetonitrile/water 1/1 (1 ml). Thissolution is applied to a column of Macro-Prep CM weak cation exchangeresin (1.5 ml). The column is eluted with 1:1 acetonitrile-water (3 ml)followed by water (3 ml). The resin is eluted with 5% aqueous sodiumchloride (6 ml) and collected in 1 ml fractions. The fractionscontaining the product are combined and treated with 5% rhodium oncarbon and stirred under an atmosphere of hydrogen. After 1.5 hour morecatalyst is added and the reduction continued for 1 hr. The catalyst isfiltered off and the filtrate is loaded onto a Rainin Microsorb C18 RPHPLC column (2×30 cm). Gradient elution with acetonitrile/0.12M aqueousammonium chloride gives pure product containing fractions which arecombined and concentrated under vacuum. The concentrated product isapplied to a column of Amberchrome CG-161 1.5 ml) which is eluted withwater (5 ml) followed by 1:1 acetonitrile-water (5 ml). Theacetonitrile-water eluate is lyophilized to give the product.

EXAMPLE 13(1S,5R,6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL2-{6-(2-(4-(4-(2-AMONIOETHYL)PHENYL)AMINOCARBONYL)METHYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-METHYL}CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Starting with the products of Preparative examples 2 and 13, andfollowing the procedure of steps 1 and 2 of Example 11, one obtains thetitle compound.

EXAMPLE 14(1S,5R,6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL2-{6-(2-(4-(2-(2-AMONIOETHYL)PHENYL)AMINOCARBONYL)METHYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-METHYL}CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Starting with the product of Preparative examples 2 and 17, andfollowing the procedure of steps 1 and 2 of Example 11, one obtains thetitle compound.

EXAMPLE 15(1S,5R,6S)-6-(1(R)-HYDROXY-ETHYL)-1-METHYL-2-{6-(2-(4-(3-(2-AMONIOETHYL)PHENYL)AMINOCARBONYL)METHYL)-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL)-1,1-DIOXO-1H-1-THIA-2-AZA-ACENAPHTHYLEN-2-YL-METHYL}CARBAPEN-2-EM-3-CARBOXYLATEDICHLORIDE

Starting with the product of Preparative Examples 16 and 2, andfollowing the procedure of steps 1 and 2 of Example 11, one obtains thetitle compound.

EXAMPLE 16 SYNTHESIS OF(1S,5R,6S)-2-{3-[2-(4-{[4-(2-AMMONIO-ETHYL)-PHENYLCARBAMOYL]-METHYL}-1,4-DIMETHYL-PIPERAZIN-1-IO)-ETHYL]-1,8-NAPHTHOSULTAMYL-METHYL}-6-[(1R)-HYDROXY-ETHYL]-1-METHYL-CARBAPENEM-2-EM-3-CARBOXYLATEDICHLORIDE

Step 1: Allyl(1S,5R,6S)-2-{3-[2-(4-{[4-(2-allyloxycarbonylamino-ethyl)-phenylcarbamoyl]-methyl}-1,4-dimethyl-piperazin-1-io)-ethyl]-1,8-naphthosultamyl-methyl}-6-[(1R)-allyloxycarbonyloxy-ethyl]-1-methyl-carbapenem-2-em-3-carboxylatebis(trifluoromethanesulfonate)

A solution of allyl(1S,5R,6S)-6-[(1R)-(allyloxycarbonyloxy)-ethyl]-1-methyl-2-{3-[3-(trifluoromethanesulfonyloxy)-propyl]-1,8-naphthosultamyl-methyl}-carbapen-2-em-3-carboxylate(0.172 mmol) in anhydrous acetonitrile (0.9 mL) is treated with allylN-(2-{4-[2-(1,4-dimethylpiperazinium)-acetylamino]-phenyl)-ethyl)-carbamatetrifluoromethanesulfonate (98 mg, 0.188 mmol). The solution kept at roomtemperature for one 20 hour then stored in a freezer at −10° C. for 4.5days. The solvent is evaporated under vacuum. The residual oil istriturated with diethyl ether, the solvent decanted, and the residuedried under vacuum to afford the title compound as a foam. It is used inthe next step without further purification.

Step 2:(1S,5R,6S)-2-{3-[2-(4-{[4-(2-ammonio-ethyl)-phenylcarbamoyl]-methyl}1,4-dimethyl-piperazin-1-io)-ethyl]-1,8-naphthosultamyl-methyl}-6-[(1R)-hydroxy-ethyl]-1-methyl-carbapenem-2-em-3-carboxylate dichloride

A solution of crude allyl(1S,5R,6S)-2-{3-[2-(4-{[4-(2-allyloxycarbonylamino-ethyl)-phenylcarbamoyl]-methyl}-1,4-dimethylpiperazin-1-io)-ethyl]-1,8-naphthosultamyl-methyl}-6-[(1R)-allyloxycarbonyloxy-ethyl]-1-methyl-carbapenem-2-em-3-carboxylatebis(trifluoromethanesulfonate) (0.172 mmol) andtetrakis(triphenylphosphine)palladium(0) (10.0 mg, 0.086 mmol) inanhydrous dimethylformamide (0.86 mL) is placed under a nitrogenatmosphere and treated with phenylsilane (0.191 mL, 1.55 mmol). Afterstirring for 20 minutes at room temperature, the solution is added todiethyl ether (13 mL) to give a precipitate. The supernatant is decantedand the solid residue dried under vacuum.

The solid is dissolved in 1:1 acetonitrile-water (3 mL) with addedtetrahydrofuran (4 mL) and water (0.5 mL) and applied to a column ofMacro-Prep CM weak cation exchange resin (2.5 mL). The column is elutedwith 1:1 acetonitrile-water (7 mL), water (12 mL), and 1:1isopropanol-10% aqueous NaCl (8 mL). The product containing fractions(1:1 iPrOH-10% NaCl) are concentrated under vacuum to a hazy suspensionand applied to a column of Amberchrom CG-161 resin (4 mL). The column iseluted with water (15 mL) followed by 20% isopropanol in water (6 mL).The product containing fractions (20% iPrOH) are concentrated undervacuum and lyophilized to give the title compound.

What is claimed is:
 1. A compound represented by formula I:

as well as pharmaceutically acceptable salts thereof, wherein allcompounds which have one or more cations are balanced with one or more,as necessary, of a charge balancing group X− or carboxylate anion: R¹represents H or methyl; CO₂M represents a carboxylic acid, a carboxylateanion, or a pharmaceutically acceptable ester group; P representshydrogen, hydroxyl, or F; A-Q-L-B represents a side chain wherein: A isa C₁₋₆ alkylene group, straight or branched, and optionally interruptedor terminated by 1-2 of —O—, —S—, NR^(a)—, —C(O)— and —CH═CH—; Qrepresents

 in which: b is 2 or 3; and X− is a charge balancing group; L representsa C₁₋₈ alkylene group, unsubstituted or substituted with 1-3 R^(c)groups, and is interrupted or terminated by 1-3 of —CH═CH—, —C(O)—,—C(O)NR_(d)—, —Het(R^(e))—, —C(O)—Het(R^(e))—, —C(O)NR^(a)—Het(R^(e))—,—O—, —S—, —S(O)—, —SO₂—, —CO₂—, —NR^(a), —N⁺(R^(a))₂—,

Het is a heteroaryl group; B represents

 wherein

represents a 5-10 membered mono- or bicyclic, N-containing heteroaryliumgroup, optionally containing 1-4 additional heteroatoms selected from O,S and N; R^(a) is H or C₁₋₆ alkyl; R^(b) is NH₂ or C₁₋₆ alkylunsubstituted or substituted with 1-3 groups selected from halo, OH, CNand C(O)NH₂; R^(c) is independently selected from halo, OR_(a), SR^(a),OC(O)R^(a), CO₂R^(a), CN, C(O)N(R^(a))₂ and C(O)R^(a), R_(d) is H orC₁₋₃ alkyl, or R^(c) and R_(d) taken together with any intervening atomsand additional carbon atoms; represent a 4-6 membered heterocyclic ring;R^(e) is H; R^(c); NO₂; N(R^(a))₂; SO₂N(R^(a))₂ or C₁₋₄ alkyl,unsubstituted or substituted with 1-3 groups selected from halo, OH andC(O)NH₂; R^(f), R^(g) and R^(h) are independently selected from H; C₁₋₆straight or branched chain alkyl, unsubstituted or substituted with 1-3R^(c) groups; C₃₋₆ cycloalkyl, unsubstituted or substituted with 1-3R^(c) groups; phenyl, unsubstituted or substituted with 1-3 R^(e) groupsand Het, unsubstituted or substituted with 1-3 R^(e) groups, or R^(f)and Rg taken together with the intervening N atom and additional carbonatoms represent a 4-6 membered heterocyclic ring, optionally interruptedby 1-2 of O, S, C(O) or NR^(h), and optionally substituted by 1-3 R^(c)groups; and each R independently represents H; NO₂; N(R^(a))₂;SO₂N(R^(a))₂; R^(c) or C₁₋₄ alkyl, unsubstituted or substituted with 1-3groups selected from halo, OH, C(O)NH₂.
 2. A compound in accordance withclaim 1 wherein R¹ represents methyl.
 3. A compound in accordance withclaim 1 wherein CO₂M represents a carboxylate anion.
 4. A compound inaccordance with claim 1 wherein P represents hydroxyl or hydroxylprotected by a hydroxyl protecting group.
 5. A compound in accordancewith claim 1 wherein A represents C1-3 alkylene.
 6. A method of treatingor preventing a bacterial infection in a mammalian patient in needthereof, comprising administering to said patient an antibacteriallyeffective amount of a compound as described in claim
 1. 7. A compound inaccordance with claim 1 wherein L is C₁₋₅ alkylene that is interruptedor terminated by —C(O)NR^(d)—, —C(O)NR^(a)—Het(R^(e))—, NR^(a),—N⁺(R^(a))₂ or


8. A compound in accordance with claim 1 wherein B represents


9. A compound represented by formula I

or a pharmaceutically acceptable salt or hydrate thereof wherein allcompounds which have one or more cations are balanced with one or more,as necessary, of a charge balancing group X− or carboxylate anion: R¹represents methyl; CO₂M represents a carboxylate anion; P representshydroxyl, A represents C₁₋₃ alkylene; Q represents

X− is a charge balancing group of no more than 2 counterions thatprovides overall charge balancing to the compound; L is C₁₋₅ alkylene,interrupted or terminated by —C(O)NR^(d)—, —C(O)NR^(a)—Het(R^(e))—,—NR^(a)—, N⁺(R^(a))₂— or

R^(a) is H or C₁₋₆ alkyl; R^(b) is NH₂ or C₁₋₆ alkyl unsubstituted orsubstituted with 1-3 groups selected from halo, OH, CN and C(O)NH₂;R^(c) is independently selected from halo, OR_(a), SR^(a), OC(O)R^(a),CO₂R^(a), CN, C(O)N(R^(a))₂ and C(O)R^(a), R^(d) is H or C₁₋₃ alkyl, orR^(c) and R^(d) taken together with any intervening atoms and additionalcarbon atoms represent a 4-6 membered heterocyclic ring; R^(e) is H;R^(c); NO₂; N(R^(a))₂; SO₂N(R^(a))₂ or C₁₋₄ alkyl, unsubstituted orsubstituted with 1-3 groups selected from halo, OH and C(O)NH₂; R^(f),Rg and R^(h) are independently selected from H; C₁₋₆ straight orbranched chain alkyl, unsubstituted or substituted with 1-3 R^(c)groups; C₃₋₆ cycloalkyl, unsubstituted or substituted with 1-3 R^(c)groups; phenyl, unsubstituted or substituted with 1-3 R^(e) groups andHet, unsubstituted or substituted with 1-3 R^(e) groups, or R^(f) and Rgtaken together with the intervening N atom and additional carbon atomsform a 4-6 membered heterocyclic ring, optionally interrupted by 1-2 ofO, S, C(O) or NR^(h), and optionally substituted by 1-3 R^(c) groups;and each R independently represents H; NO₂; N(R^(a))₂; SO₂N(R^(a))₂;R^(c) or C₁₋₄ alkyl, unsubstituted or substituted with 1-3 groupsselected from halo, OH, C(O)NH₂, or R together with A of the group-A-Q-L-B and any intervening atoms and additional carbon atoms representa 5-6 membered heterocyclic ring-containing structure, wherein theheterocyclic ring-containing structure fuses to the naphthosultamyl ringat adjacent carbons of positions 2 through
 7. 10. A compound representedby one of Tables I-III, as well as pharmaceutically acceptable saltsthereof, wherein all compounds which have one or more cations arebalanced with one or more, as necessary, of a charge balancing group X—or carboxylate anion: TABLE I

wherein Q-L-B is selected from:

TABLE II

wherein Q-L-B is selected from:

TABLE III

wherein Q-L-B is selected from:

wherein X⁻ represents a countenion.
 11. A pharmaceutical compositionwhich is comprised of a compound in accordance with claim 1 incombination with a carrier.